Halogenated Phenols for Diagnostics, Antioxidant Protection and Drug Delivery

ABSTRACT

The present invention provides compositions and methods for the targeted delivery, release and/or formation of a drug compound at a target site(s) within the body of an individual, such as a diseased and/or inflamed tissue in the body of the individual. These compositions may comprise a halogenated phenol ring cleavably linked to a core structure of a drug compound. Due to the variety of substituents that may be utilized in forming the different types of linkages, numerous examples of drug compounds linked to a halogenated phenol ring are proposed. The present invention further provides compositions comprising halogenated phenol starting compounds that do not undergo cleavage during a dehalogenation reaction to form a drug compound in a targeted tissue when administered to an individual. Methods of administering these non-cleaving compounds are further provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application claiming the benefit ofpriority to U.S. patent application Ser. No. 13/548,358 entitled“Halogenated Phenol Ethers for Diagnostics and Drug Delivery,” filed onJul. 13, 2012, which further claims the benefit of priority to U.S.Provisional Patent Application No. 61/507,670, entitled “HalogenatedPhenol Ethers for Diagnostics and Drug Delivery,” filed on Jul. 14,2011. The entire contents and disclosures of the above applications areincorporated herein by reference.

BACKGROUND Field of the Invention

The present invention relates generally to compositions and methods fortargeted delivery and release of drug compounds at sites of inflammationand/or disease within the body of an individual.

Related Art

Site-specific delivery of drug compounds has generally been achievedeither by local administration of the compound directly into a targetsite or by conjugation of the drug compound to specific targetingmolecules or carriers. These targeting molecules or carriers generallyinclude specific ligands, such as peptides, proteins, sugars, etc.,which may bind to specific receptors or other molecules present attarget sites, or antibodies having specific affinity for receptors orother cell surface markers present at target sites. Targeting moleculesor carriers may be associated with drug-containing liposomes or othervesicles, micelles, etc., to achieve targeted delivery of the drug.Other specialized approaches for targeted delivery of drugs have beenproposed as well. However, in many cases these antibody, ligand, orvesicle-based targeting approaches may not effectively distinguishbetween diseased and normal tissue and may have difficulty crossing theblood-brain barrier.

There continues to be a need in the art for the development of new andimproved techniques and compositions for the targeted delivery of drugsto sites of disease and/or inflammation within the body of an individualto treat or alleviate the condition.

SUMMARY

According to a first broad aspect of the present invention, compositionsare provided comprising a starting compound of the present invention asshown, for example, in FIGS. 1-19 including a halogenated phenol ringcleavably linked to a core structure of a drug compound. Methods ofadministering these compositions to an individual are further provided,which may result in the drug compound being liberated and released in atargeted tissue in the presence of FROS. Numerous examples of drugcompounds linked to a halogenated phenol ring are provided. The natureof the linkage to the halogenated phenol ring may vary and maypotentially include an ether linkage, a thioether linkage, a nitrogenlinkage, an internal nitrogen linkage, a carbonyl linkage, a sulfinyllinkage, a metal linkage or even possibly a C—C bond depending on thedrug compound.

According to a second broad aspect of the present invention,compositions are provided comprising a starting compound of the presentinvention as shown, for example, in FIGS. 26 and 27 including ahalogenated phenol ring, wherein the starting compound differs from thestructure of a drug compound only in that a hydroxyl group on a phenolring of the drug compound is replaced with a halogen. Due to the natureof the starting compound, however, cleavage does not occur withdehalogenation. Thus, the drug compound is produced or reconstituted bythe dehalogenation reaction without cleavage. Methods of administeringthese compositions to an individual are further provided, which mayresult in the drug compound being formed in a targeted tissue in thepresence of FROS.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated herein and constitutepart of this specification, illustrate exemplary embodiments of theinvention, and, together with the general description given above andthe detailed description given below, serve to explain the features ofthe invention.

FIG. 1 is a diagram of a dehalogenation and cleavage reaction accordingto formula embodiments of the present invention with an ether orthioether linkage;

FIG. 2 is a diagram of a dehalogenation and cleavage reaction accordingto formula embodiments of the present invention with an ether orthioether linkage;

FIG. 3 is a diagram of a dehalogenation and cleavage reaction accordingto formula embodiments of the present invention with an ether orthioether linkage;

FIG. 4 is a diagram of a dehalogenation and cleavage reaction accordingto formula embodiments of the present invention with an ether orthioether linkage;

FIG. 5 is a diagram of a dehalogenation and cleavage reaction accordingto formula embodiments of the present invention with two drugs ether orthioether linked to the ring;

FIG. 6A is a diagram of a first dehalogenation and cleavage reaction ofa two-step reaction according to formula embodiments of the presentinvention for sequential release of two drugs ether or thioether linkedto the ring;

FIG. 6B is a diagram of a second dehalogenation and cleavage reaction ofa two-step reaction according to formula embodiments of the presentinvention for sequential release of two drugs ether or thioether linkedto the ring;

FIG. 7 is a diagram of a series of dehalogenation and cleavage reactionsto occur with a formula of polymer embodiments of the present invention,which may result in successive release of drugs from respectivemonomers;

FIG. 8A is a diagram of a dehalogenation and cleavage reaction accordingto an embodiment of the present invention for the formation of dopamine;

FIG. 8B is a formula of a starting compound according to an embodimentof the present invention for the formation of L-DOPA;

FIG. 9 is a diagram of a dehalogenation and cleavage reaction accordingto an embodiment of the present invention for the formation ofestradiol;

FIG. 10 is a diagram of a dehalogenation and cleavage reaction accordingto an embodiment of the present invention for the formation ofserotonin;

FIG. 11A is a diagram of a dehalogenation and cleavage reactionaccording to an embodiment of the present invention for the formation ofacetaminophen; FIG. 11B is a diagram of a dehalogenation and cleavagereaction according to an embodiment of the present invention for theformation of dihydromorphinone; FIG. 11C is a diagram of adehalogenation and cleavage reaction according to an embodiment of thepresent invention for the formation of morphine;

FIG. 12 is a diagram of a dehalogenation and cleavage reaction accordingto an embodiment of the present invention for the formation of cysteine;

FIG. 13 is a diagram of a dehalogenation and cleavage reaction accordingto an embodiment of the present invention for the formation ofcortisone;

FIG. 14 is a diagram of a dehalogenation and cleavage reaction accordingto an embodiment of the present invention for the formation of5-iodo-uracil;

FIG. 15 is a diagram of a dehalogenation and cleavage reaction accordingto formula embodiments of the present invention with a nitrogen linkage;

FIG. 16 is a diagram of a dehalogenation and cleavage reaction accordingto an embodiment of the present invention for the formation ofmethotrexate;

FIG. 17 is a diagram of a dehalogenation and cleavage reaction accordingto formula embodiments of the present invention with a carbonyl linkage;

FIG. 18 is a diagram of a dehalogenation and cleavage reaction accordingto an embodiment of the present invention for the formation ofpenicillin;

FIG. 19A is a diagram of a dehalogenation and cleavage reactionaccording to an embodiment of the present invention for the formation ofaspirin;

FIG. 19B is a diagram of a dehalogenation and cleavage reactionaccording to an embodiment of the present invention for the formation ofnaproxen;

FIG. 19C is a diagram of a dehalogenation and cleavage reactionaccording to an embodiment of the present invention for the formation ofibuprofen;

FIG. 20 is a diagram of a dehalogenation and cleavage reaction accordingto formula embodiments of the present invention with a C—C bond;

FIG. 21 is a diagram of a dehalogenation and cleavage reaction accordingto formula embodiments of the present invention for use as anantioxidant and/or free radical scavenger;

FIG. 22 is a diagram of a dehalogenation and cleavage reaction accordingto a compound embodiment of the present invention using reverse T3 as anantioxidant and/or free radical scavenger;

FIG. 23A is a diagram of a dehalogenation and cleavage reactionaccording to diphenyl formula embodiments of the present invention withan ether or thioether linkage; FIG. 23B is a diphenyl formula forembodiments of the present invention with a nitrogen linkage; FIG. 23Cis a diphenyl formula for embodiments of the present invention with acarbonyl linkage; FIG. 23D is a diphenyl formula for embodiments of thepresent invention with a C—C bond;

FIG. 23E is a diagram of a dehalogenation and cleavage reactionaccording to dihydroxy diphenyl formula embodiments of the presentinvention with an ether or thioether linkage; FIG. 23F is a dihydroxydiphenyl formula for embodiments of the present invention with anitrogen linkage; FIG. 23G is a dihydroxy diphenyl formula forembodiments of the present invention with a carbonyl linkage; FIG. 23His a dihydroxy diphenyl formula for embodiments of the present inventionwith a C—C bond;

FIG. 24 is a diagram of a dehalogenation and cleavage reaction accordingto a compound embodiment of the present invention(3-iodo-4,4′-dihydroxy-diphenyl ether) for use as an antioxidant and/orfree radical scavenger;

FIG. 25 is a diagram of a dehalogenation and cleavage reaction with aformula for a polymer embodiment of the present invention for use as anantioxidant and/or free radical scavenger;

FIG. 26 is a diagram of a dehalogenation reaction without cleavageaccording to formula embodiments of the present invention;

FIG. 27 is a diagram of a dehalogenation reaction without cleavageaccording to a compound embodiment of the present invention; and

FIG. 28A is a formula for indigogenic embodiments of the presentinvention for the production of a detectable product for diagnosticpurposes;

FIG. 28B is a diagram of a dehalogenation and cleavage reactionaccording to a formula of indigogenic compounds of the present inventionfor the formation of detectable or radioisotope-carrying indigo-likecompounds that may have higher residence times in target FROS-containingtissues;

FIG. 29A is an indigogenic compound embodiment of the present inventioncontaining a bromine and chlorine to produce a detectably coloredindigo-like product; FIG. 29B is an indigogenic compound embodiment ofthe present invention containing an iodine to produce a detectable andradio-opaque indigo-like product; and FIG. 29C is an indigogeniccompound embodiment of the present invention containing two iodines toproduce a detectable and radio-opaque indigo-like product; and

FIG. 30 is a pair of images showing radio-opaque sites of formation ofan indigo-like product with an administered indigogenic compound, whichare absent prior to administration of the indigogenic compound.

DETAILED DESCRIPTION Definitions

Where the definition of terms departs from the commonly used meaning ofthe term, applicant intends to utilize the definitions provided below,unless specifically indicated.

For purposes of the present invention, the term “halogenated phenolring” refers to at least a portion of an arene molecule or compoundhaving a benzene ring and a hydroxyl group and a halogen as substituentsbonded to adjacent carbons of the benzene ring.

For purposes of the present invention, the terms “arene” or “arenes”refer to organic molecules or compounds based on the aromatic benzenering as a structural unit.

For purposes of the present invention, the term “linkage” refers to achemical linkage or bond(s) of a starting compound that connects ahalogenated phenol ring to a compound, such as a drug compound. Asdescribed further herein, the “linkage” may be an ether linkage,thioether linkage, nitrogen linkage, an internal nitrogen linkage, acarbonyl linkage, a sulfinyl linkage, a metal linkage or possibly a C—Cbond. According to some embodiments, this linkage is cleaved or brokenduring or following the dehalogenation reaction involving the startingcompound.

For purposes of the present invention, the terms “ether linkage,” “ethergroup,” and “ether linked” refer to a functional group of a compound,such as a starting compound of the present invention, consisting of anoxygen atom singly bonded to two carbons of the compound (i.e., R—O—R′).For example, an “ether linkage” may join a halogenated phenol ring (R)to a core structure (R′) of a compound.

For purposes of the present invention, the terms “thioether linkage,”“thioether group,” and “thioether linked” refer to a functional group ofa compound, such as a starting compound of the present invention,consisting of an sulfur atom singly bonded to two carbons of thecompound (i.e., R—S—R′). For example, a “thioether linkage” may join ahalogenated phenol ring (R) to a core structure (R′) of a compound.

For purposes of the present invention, the terms “carbonyl linkage,”“carbonyl group” or “carbonyl linked” refer to a functional group of acompound, such as a starting compound of the present invention,consisting of a carbon doubly bonded to an oxygen and singly bonded totwo carbons of the compound (i.e., R—[C═O]—R′, with the R, R′ eachbonded to the C). For example, a “carbonyl linkage” may join ahalogenated phenol ring (R) to a core structure (R′) of a compound.

For purposes of the present invention, the terms “sulfoxide linkage,”“sulfinyl linkage,” “sulfinyl group” or “sulfinyl linked” refer to afunctional group of a compound, such as a starting compound of thepresent invention, consisting of a sulfur atom doubly bonded to anoxygen and singly bonded to two carbons of the compound (i.e.,R—[S═O]—R′, with the R, R′ each bonded to the S). For example, a“sulfoxide linkage” may join a halogenated phenol ring (R) to a corestructure (R′) of a compound.

For purposes of the present invention, the terms “nitrogen linkage” and“nitrogen linked” refer to a functional group of a secondary aminecompound, such as a starting compound of the present invention,consisting of a nitrogen atom singly bonded to a hydrogen and twoR-groups of the compound (i.e., R— NH—R′, with the R, R′ each bonded tothe N). For example, a “nitrogen linkage” may join a halogenated phenolring (R) to a core structure (R′) of a compound. In some instances, a“nitrogen linkage” may further include an alternate nitrogen linkageconsisting of a nitrogen atom singly bonded to two hydrogens and twoR-groups of a compound, such as a starting compound of the presentinvention, (i.e., R— NH₂—R′, with the R, R′ each bonded to the N) due tothe particular chemical features of the compound that permits four bondswith the nitrogen. The nitrogen of this alternate nitrogen linkage maybe positively charged.

For purposes of the present invention, the terms “internal nitrogenlinkage” or “internal nitrogen linked” refer to a nitrogen of a tertiaryamine compound, such as a starting compound of the present invention,consisting of a nitrogen atom singly bonded to three R-groups of thecompound (i.e., R, R′, R″ each bonded to the N). For example, an“internal nitrogen linkage” may join a halogenated phenol ring (R) to acore structure (R′—N—R″) of a compound with the nitrogen (N) of the“internal nitrogen linkage” forming part of the core structure of thecompound.

For purposes of the present invention, the terms “metal linkage” refersto a bond directly between a first R-group and a metal or metalloid atomor element (as identified in the periodic table). The metal or metalloidelement may be part of a second R-group (R′). For example, the metalatom or element may include boron (B) or mercury (Hg). In the case ofboron, for example, the boron atom may be able to directly bond to threeR-groups (i.e., R, R′, R″ each bonded to the B), one or more of whichmay include a halogenated phenol ring. In other cases, such as withmercury, the metal atom (i.e., Hg) directly bonded to the first R-groupmay be ionized, which may also pair with an anion to form a salt. Ametal linkage between a halogenated phenol ring and the metal ormetalloid atom or element (which may be part of an R′-group) may becomecleaved in a dehalogenation to release the metal or metalloid atom orelement that may be part of the R′-group.

For purposes of the present invention, the terms “oxidizing agent” or“oxidative agent” or “oxidizing species” or “oxidative species” referinterchangeably to a substance or compound that accepts an electron(s)from another substance or compound in an oxidation-reduction (redox)reaction. During the redox reaction, the oxidizing agent is reducedwhile the other substance or compound is oxidized.

For purposes of the present invention, the terms “oxidizing stress” or“oxidative stress” refer interchangeably to a state or condition in atissue or cellular environment having an elevated level of oxidizingagents relative to a normal or controlled state or condition for suchtissue or cellular environment. For example, such oxidative stress maybe associated with inflamed and/or diseased cells or tissues.

For purposes of the present invention, the terms “free radical” or “freeradicals” refer to reactive substances or molecules having one or moreunpaired electron(s).

For purposes of the present invention, the term “free radical stress”refers to a state or condition in a tissue or cellular environmenthaving an elevated level of free radicals relative to a normal orcontrolled state or condition for such tissue or cellular environment.For example, such free radical stress may be associated with inflamedand/or diseased cells or tissues.

For purposes of the present invention, the terms “chemical group,”“functional group,” or “group” with regard to chemical compounds andcompositions refer interchangeably to an atom or a group of atoms bondedtogether that form part of the chemical structure of a compound.

For purposes of the present invention, the terms “substituent” or“substituents” with regard to chemical compounds and compositions referto an atom, radical, or group of bonded atoms of a chemical compoundthat may be substituted for another atom, radical, or group of bondedatoms. For example, a substituent may refer to an individual chemicalgroup bonded to a carbon, nitrogen or other atom of a chemical compound.Such a substituent may be a functional group providing physical orchemical properties to the compound.

For purposes of the present invention, the term “adjacent” with regardto the chemical structure of a compound in reference to two atoms ofthat compound refers to a first atom of a ring, such as a benzene ring,of the compound that is next to (i.e., bonded directly to) another atomof the ring. For example, the term may refer to two adjacent carbons ofa benzene ring that are bonded to one another. However, the term“adjacent” may also refer to a carbon and a nitrogen of a ring structurethat are bonded directly to each other.

For purposes of the present invention, the term “individual,” “subject,”or “patient” refer interchangeably to a mammal, such as a rat or ahuman, that may take or be administered, given or provided a compound orcomposition of the present invention but may most commonly refer to ahuman. In the case of drug delivery, such an individual may be anymammal, typically a human, having or suffering from inflammation or acondition or disease caused or mediated by, or associated with, higherlevels of free radicals and/or oxidative species (FROS), or suspected ofhaving or suffering from the same. Such an individual may also include amammal, typically a human, that is considered normal (i.e., notnecessarily suspected of having or suffering from any of the aboveconditions) when, for example, a test, screen or preventive treatment isconducted on the individual.

For purposes of the present invention, the term “starting compound” or“original compound” refer interchangeably to a compound of the presentinvention prior to becoming modified in a dehalogenation (or adehalogenation and cleavage) reaction.

For purposes of the present invention, the terms “electron donating,”“electron releasing,” “electron donor,” or “electron donating group” inreference to a substituent bonded to a carbon of the benzene ring of ahalogenated phenol ring-containing compound of the present inventionrefer to a substituent that donates electrons to or increases theelectron density of the benzene ring of the halogenated phenolring-containing compound.

For purposes of the present invention, the terms “electron withdrawing,”“electron withdrawer,” or “electron withdrawing group” in reference to asubstituent bonded to a carbon of a halogenated phenol ring-containingcompound of the present invention refer to a substituent that withdrawselectrons from or reduces the electron density of the halogenated phenolring-containing compound.

For purposes of the present invention, the terms “benzenetriol” or“benzenetriol-based” refer to compounds containing a benzene ring havingthree hydroxyl substituents bonded to the benzene ring. A“benzenetriol-based” compound may have hydrogen or substituent(s) otherthan hydrogen at the other positions of the benzene ring.

For purposes of the present invention, the terms “benzenetetrol” or“benzenetetrol-based” refer to compounds containing a benzene ringhaving four hydroxyl substituents bonded to the benzene ring. A“benzenetetrol-based” compound may have hydrogen or substituent(s) otherthan hydrogen at the other positions of the benzene ring.

For purposes of the present invention, the term “hydroquinone” refers toa compound containing a benzene ring having two para-hydroxyl groups.

For purposes of the present invention, the terms “hydroxyhydroquinone”or “hydroxyhydroquinone-based” refer to a compound containing a benzenering having three hydroxyl groups, such as 1,2,4-benzenetriol.

For purposes of the present invention, the term “indigo” refers to achemical compound having the chemical formula, C₁₆H₁₀N₂O₂ and composedto two indole heterocylic rings joined by a double bond as commonlyunderstood.

For purposes of the present invention, the term “indigo-like compound”refers to a compound having the chemical structure of indigo, but whichmay also have one or more substituents other than hydrogen on thebenzene ring(s) of one or both of the two heterocyclic indole rings. Forexample, an indigo like compound may include an indigo compound having ahalogen and/or a radioactive isotope as a substituent on the benzenering(s) of one or both of the two heterocyclic indole rings.

For purposes of the present invention, the terms “indole” or “indolecontaining compound” refer to a molecule or compound containing one ormore heterocyclic indole rings. For purposes of the present invention,the terms “indole rings” or “heterocyclic indole rings” refer to abicyclic chemical structure having a six-membered benzene ring fused toa five-membered nitrogen-containing pyrrole ring.

For purposes of the present invention, the term “residence time” refersto a property of a compound having a tendency to linger or remain in atissue or cellular environment due to its chemical properties. Acompound having a high residence time may include a hydrophobic orlipophilic compound. For example, a compound having a high residencetime may include an indigo-like compound.

For purposes of the present invention, the term “sensitivity ofcleavage” refers to a property of how easily a linkage (e.g., etherlinkage, etc.) between a compound, such as a drug compound, and ahalogenated phenol ring of a starting compound becomes cleaved or brokenin the presence of free radicals and/or oxidative agents. A startingcompound having a high sensitivity of cleavage has a low threshold ofcleavage (i.e., the linkage between the compound and the halogenatedphenol ring is easily cleaved in the presence of free radicals and/oroxidative agents). In contrast, a starting compound having a lowsensitivity of cleavage has a high threshold of cleavage (i.e., thelinkage between the compound and the halogenated phenol ring is noteasily cleaved in the presence of free radicals and/or oxidativeagents). In general, it is believed that halogenated phenol compoundshaving more destabilization of the phenol ring will have a highersensitivity of cleavage.

For purposes of the present invention, the term “infectious agent”refers to an infectious particle or organism which can infect a cell ortissue, such as a virus, bacterium, protozoan, fungus, etc.

For purposes of the present invention, a “drug compound” refers to anycompound having a known chemical structure that is currently used oradministered as an existing form of therapy for the treatment,alleviation, prevention, etc., of a disease or a physiological,veterinary or medical condition. In the case of drugs for medical use, a“drug compound” includes any such compound that is available eitherover-the-counter (OTC) or by prescription, which may be administered byany suitable route of administration. A “drug compound” for purposes ofthe present invention may include not only drug compounds that are takenor administered into the body, but also any known and anticipatedmetabolites of these drugs having a known chemical structure. Forexample, a metabolite of a taken or administered drug compound mayinclude a known “active form” of the administered drug compound having aknown chemical structure produced by chemical modification of the drugfrom its taken or administered “pro-drug” form (due to bodily mechanismsin the liver and other tissues of the individual receiving the“pro-drug” form of the drug).

For purposes of the present invention, the term “core structure” refersto the majority portion of a compound or drug compound minus (i.e.,without) the substituent that participates in forming the linkage with ahalogenated phenol ring (HPR). For example, if a drug compound (R₁—YH)is linked to a halogenated phenol ring (i.e., R₁—Y—HPR) by an ether orthioether linkage (with Y being oxygen or sulfur), then the “corestructure” of the drug compound would be R₁. Likewise, if a drugcompound (R₁—NH₂) is linked to a halogenated phenol ring (i.e.,R₁—NH-HPR) by a nitrogen linkage, or if a drug compound (R₁—COOH) islinked to a halogenated phenol ring (i.e., R₁—[C═O]-HPR) by a carbonyllinkage, or if a drug compound (R₁—CH₂OH) is linked to a halogenatedphenol ring (i.e., R₁—CH₂—HPR) by a C—C bond, or if a drug compound(R₁—SO₃H) is linked to a halogenated phenol ring (i.e., R₁—[S═O]-HPR) bya sulfinyl linkage, then (in each case) the “core structure” of the drugcompound would be R₁. Similarly, if a drug compound (R₁—H consisting ofR′—NH—R″ with R₁ the same as R′—N—R″) is linked to a halogenated phenolring (i.e., R′/R″—N-HPR or, in other words, the N singly bonded to R′,R″ and HPR) by an internal nitrogen linkage, then the “core structure”of the drug compound would be R₁ (i.e., R′—N—R″). With regard to thecore structure of a compound or drug compound, the “substituent” refersonly to the limited set of substituents on the compound or drug compoundthat are identified herein as being capable of being converted orreacted to form a linkage with a halogenated phenol ring: a hydroxyl(—OH), keto (C═O), carboxyl (—COOH), amino (—NH₂), alcohol (—CH₂OH),sulfonic acid (SO₃H) or sulfhydryl (—SH) group(s) or a hydrogen (—H)bonded to a nitrogen of a core structure (in the case of an internalnitrogen linkage).

For purposes of the present invention, the terms “empty unit” or “emptyunits” refer to a monomer or unit of a polymer of the present inventionthat is not directly bonded to a drug compound via a linkage (i.e., anether linkage, etc.).

For purposes of the present invention, the term “purify” in reference toa substance or compound in a sample means to selectively remove othercomponents from the sample relative to the amount of the substance orcompound to produce a purified sample of the substance or compound. Theterm “concentrate” in reference to a substance or compound in a samplemeans increasing the concentration of the substance or compound relativeto other components to produce a concentrated sample of the substance orcompound. In either case, the “purified sample” or “concentrated sample”may be referred to simply as a “sample” with the substance or compoundpurified or concentrated therein, respectively, from an initial ororiginal sample taken from an individual.

For purposes of the present invention, the terms “administer,”“administering,” and “administration” in reference to a composition,compound or drug mean taking, placing, putting, etc., the composition,compound or drug into the body of an individual by any method and by anyroute of administration. Such “administering” or “administration” may beperformed by the individual, a health care provider or any other person.

DESCRIPTION

Site specific drug delivery systems generally attempt to exploit uniquecharacteristics of target tissues or cells. In addition to targetingspecific cell surface markers or achieving targeted delivery throughlocal administration, drug delivery systems have been proposed torelease drugs or therapeutics under specific chemical conditions (e.g.,altered pH, temperature, etc.) that may exist in a target tissue. Otherspecialized approaches for targeted delivery of drugs (e.g., use ofexternal magnets with magnetic carriers) have also been proposed. See,e.g., Torchlin, V. P., “Drug Targeting.” Eur. J. Pharm. Sci., 11 (Suppl2): S81-91 (2000). The present invention provides for the targeteddelivery and release of a drug or therapeutic compound to sites ofinflamed, diseased, neoplastic, metastatic, infected, etc., cells ortissue, which are generally characterized by high levels of oxidizingagents and/or free radicals resulting from the inflammation or pathologyof the targeted cells or tissue.

Various diseases and conditions are associated with affected cells andtissues (including diseased cells and tissues, such as tumors, etc.)becoming hypermetabolic. This hypermetabolism may lead to elevatedlevels of free radicals and/or oxidative species (FROS) in those cellsand tissues, which may be due in part to the release of these FROS from“leaky” mitochondria. Such hypermetabolism may be evidenced by weightloss, cachexia, etc., and referred to as “free radical catastrophe” inextreme cases. Many conditions or disease states may also lead tohyperthyroidism, which may also increase the rate of metabolism inaffected tissues or cells. In addition, sites of immunity andinflammation, which may be associated with tissue injury,transplantation rejection or other diseases, may also lead to conditionsof increased FROS within those tissues and be amenable to treatment bypresent embodiments. These diseases and conditions may thus be amenableto treatment, prevention, etc., according to embodiments of the presentinvention, which as described below, may be used to provide targeteddelivery of drug compound(s) and/or other activities at sites of highFROS.

Hypometabolic events associated with ischemia may also result in FROSgeneration. For example, myocardial infarct and stroke may result in atleast temporary, localized ischemic deprivation of oxygen and nutrients,resulting in metabolic failure and depletion of natural FROS quenchingmechanisms. Failure of mitochondrial integrity can also result in FROSgeneration through membrane leakage and hyper-compensatory metabolicresponses. Reperfusion of such ischemic tissues, as a standard course oftherapy, can also result in further FROS damage to the tissues affected.The combination of depleted FROS defenses and/or increased FROS can leadto cellular or tissue damage or death. Thus, embodiments of the presentinvention may also be beneficially applied in these contexts to helpprotect or rescue these tissues during or following these events. Forexample, compound embodiments may be administered in conjunction withreperfusion therapy.

According to embodiments of the present invention, these properties ofdiseased and/or inflamed cells or tissues are exploited by designingcompounds that will provide targeted release and unmasking of drugcompounds at these high FROS sites within the body of an individual. Asdescribed further below, such compounds may generally comprise a drugcompound conjugated to a halogenated phenol ring via a chemical linkage,which may include an ether, thioether, carbonyl, sulfinyl, nitrogen,internal nitrogen or possibly a C—C bond or linkage. When such acompound of the present invention comes in contact with, or is presentwithin, an oxidizing and/or free radical containing environment, such asin a diseased and/or inflamed tissue, a spontaneous reaction may occurresulting in cleavage of the chemical linkage and release of theliberated drug compound from the halogenated phenol ring. Because thiscleavage reaction involves the consumption of free radicals or oxidativespecies (FROS), it is further proposed that compounds of the presentinvention may also be used as FROS scavengers. In addition, thiscleavage reaction may also be used for diagnostic purposes as a basisfor releasing or forming detectable compounds as an indicator of highFROS systemically in the body or in specific tissues.

Enzymatic reductive deiodination of thyroid hormones, replacing thecovalently bound iodine of the thyronine nucleus with a hydrogen, hasbeen observed. See, e.g., Leonard, J. et al., The Thyroid,Lippincott-Raven (Braverman, L. E. and Utiger, R. D., Eds.), pp. 125-161(1996), the contents and disclosure of which is incorporated herein byreference. For example, thyroxine may be converted to3,5,3′-triiodo-L-thyronine (T3) by this process. However, reductivedeiodination is contrary to the present invention which describes anoxidative process in which the halogen (i.e., iodine) is removed andreplaced with a hydroxyl group along with cleavage of the relevantlinkage or bond, such as an ether linkage, etc. It is proposed that thischemical mechanism may be utilized in the design of new targeted drugsand the development of new therapeutic and diagnostic approaches. Thegeneral use of this oxidative and/or free radical process according tothe present invention may define a new platform or paradigm, which maybe referred to as Oxidative or Free Radical Medicine to distinguish itfrom other therapeutic approaches.

In contrast to reductive deiodination, spontaneous dehalogenation (e.g.,deiodination) of a halogentated phenol ring in the presence of anoxidizing agent(s) and/or free radical(s) with cleavage of a chemicallinkage, such as an ether linkage, etc., between the phenol ring and aconjugated compound has not been described. According to the presentinvention, cleavage of the ether linkage between the aromatic rings ofthyroid hormone may form visibly colored quinone and iodine-containingproducts in buffered aqueous solutions in vitro, and this ether cleavagereaction may be accelerated under basic pH conditions and with exposureto ionizing radiation or light. These conditions favor the increasedformation of oxidizing agents and/or free radicals, which are believedto promote the reaction. For example, it has been discovered that ifabout 1 mM of thyroxine is dissolved in carbonate buffer (pH 8.0) andexposed to sunlight for about one hour, the ether linkage is brokenspontaneously, and a clear yellow/orange solution is formed as iodide isreleased from the phenolic n-ring. A quinone and an iodotyrosine productare also formed by cleavage of the ether linkage during the reaction.According to embodiments of the present invention, a spontaneousreaction of dehalogenation and cleavage of a chemical bond is proposedfor the targeted delivery and release of a drug compound at or to sitesof inflammation or disease. This spontaneous reaction is furtherproposed as a basis for scavenging free radicals and/or oxidative agents(FROS) as well as for the creation of a detectable compound(s) that maybe used for diagnostic purposes.

The discovery that an ether linkage between a halogentated phenol ringand a conjugated compound becomes cleaved upon dehalogenation of thehalogenated phenol ring in the presence of oxidizing agents and/or freeradicals is unexpected since ether linkages are considered to beespecially stable (i.e., a bond energy of greater than about 200kcal/mol), compared to C—C bonds (i.e., about 102 kcal/mol) and C—Hbonds (i.e., about 80 kcal/mol), which are also regarded as stablebonds. However, it has been found that following supposed free radicalattack of the phenol ring, the ether linkage becomes surprisingly labileand is subsequently cleaved to reach a lower energy state.

It has also been discovered that other types of bonds or linkages mayalso be cleaved by oxidative or free radical-mediated dehalogenation ofthe phenol ring. For example, as described herein, it has now beenobserved that a carbonyl linkage, a nitrogen linkage, a sulfinyl linkageand possibly a C—C bond on the phenol ring may also be cleaved by theoxidative dehalogenation reaction. These bonds are also consideredstable, and their cleavage in connection with the dehalogenationreaction is surprising as well. One caveat with the C—C bond or linkageis that depending on the particular starting compound structure and thesubstituents or groups attached to the halogenated phenol ring via theC—C bond, the C—C bond or linkage may or may not be generally cleavedduring or following the dehalogenation reaction (see below). Forexample, mono-iodotyrosine (MIT) discussed below is found generally notto be cleaved with the reaction. However, other compounds do becomecleaved. It is important to note that whether a C—C bond of a particularstarting compound is “cleavable,” or becomes cleaved, may not beall-or-nothing (i.e., the C—C bond may be considered non-cleavable eventhough a small or minute amount of cleavage may occur, and vice versa).Thus, the amount or percentage of cleavage may be partial with thealternatively cleaved or non-cleaved product being possibly undetectedor minute.

Without being bound by any theory, it is believed that upon free radicalattack or oxidation of the halogen bond of a halogenated phenol ring,the halogen becomes removed and replaced with a hydroxyl and changesoccur to the cloud of electrons within the phenol ring. These changes tothe electron cloud are believed to result in the bond or linkage (e.g.,ether linkage, carbonyl linkage, etc.) connecting the conjugatedcompound to the ring to become labile, which may ultimately becomecleaved (and replaced with another hydroxyl group). For this chemistryto work, water molecules (or their ions) from a surrounding aqueousenvironment are needed to supply the hydroxyl groups added to the ringduring the reaction, as well as hydrogen(s), oxygen(s) and/orhydroxyl(s) that may be added to the (drug) compound cleaved from thering. This requirement for an aqueous environment is met underphysiological conditions, making this technology suitable forpharmaceutical applications. It is further observed that linkages atpositions further away from the hydroxyl group on the halogenated phenolring may generally tend to be more sensitive to cleavage, which mayreflect the spatial reorganization of the electron cloud that takesplace during or following the dehalogenation reaction. Thus, the paraposition relative to the hydroxyl may be the most sensitive to cleavage,as compared to the meta and ortho positions. However, the exact changesto the electron cloud during or following the dehalogenation reaction(and the sensitivity at any one position) may depend on othersubstituents present on the phenol ring.

According to a first broad aspect of the present invention, it isproposed that the oxidation and/or free radical mediated cleavagereaction may be generally applied to a wide variety of drug compound(s)linked, bonded, conjugated, etc., to a halogenated phenol ring by anether, thioether, carbonyl, sulfinyl, nitrogen, internal nitrogen or C—Cbond or linkage to form (starting) compounds of the present invention.These starting compounds comprising a halogenated phenol ring conjugatedor linked to the drug compound may be used to achieve site-specificdelivery and targeted release of the drug compound(s) to locationswithin the body of an individual experiencing or having elevated levelsof oxidative and/or free radical stress, which are often associated withdiseased and/or inflamed cells or tissues. For the reaction to workeffectively, the halogen substituent bonded to the phenol ring of thestarting compound of the present invention needs to be adjacent to(i.e., in the ortho position relative to) the hydroxyl group orsubstituent of the phenol ring. However, the linkage(s) between thephenol ring and the drug compound(s) of the starting compound of thepresent invention, may potentially be positioned anywhere on the phenolring not occupied by the halogen and hydroxyl group (i.e., bonded to anyone of the four remaining carbons on the phenol ring), and a variety ofdifferent chemical groups or substituents may be bonded to the remainingcarbons of the phenol ring.

According to embodiments of the present invention, the linkage betweenthe halogenated phenol ring and a linked compound, such as a drugcompound, may comprise: an ether linkage or group (—O—), a thioetherlinkage or group (—S—), a carbonyl linkage or group (—[C═O]—), asulfinyl linkage or group (—[S═O]—), a nitrogen linkage or group (—NH—),or possibly a C—C bond. The linkage may also include an internalnitrogen linkage if a nitrogen of a secondary amine (drug) compound islinked to the halogenated phenol ring (to form a starting compoundhaving a tertiary amine structure). However, for a linked compound, suchas a drug compound, to become covalently bonded to the halogenatedphenol ring, such compound must contain at least one suitablesubstituent capable of forming one of these types of bonds or linkages.Thus, the linked (drug) compound may include any such compound havingone or more of: a hydroxyl (—OH), a keto (C═O), a carboxyl (—COOH), anamino (—NH₂), an alcohol (—CH₂OH), a sulfonic acid (—SO₃H) or asulfhydryl (—SH) group, or a hydrogen (—H) bonded to an “internal”nitrogen of a secondary amine (drug) compound, which is capable of beingconverted or used to form one of the respective cleavable linkageslisted above with the halogenated phenol ring.

Compounds or drug compounds having a keto group in their most stableform may be ether linked to the halogenated phenol ring in somecircumstances. A compound having (i) a keto group and (ii) an adjacentsingle bond that may be engineered into a double bond, may be etherlinked to a halogenated phenol ring via the carbon having the ketogroup. This approach relies on the carbon of the keto group (of the(drug) compound) to have the engineered double bond with an adjacentcarbon. Although a hydroxyl group may be initially formed by thecleavage reaction on the carbon at the ether linkage position, thishydroxyl group may then spontaneously resonate or tautomerize with theadjacent double bond to form the keto group on the liberated (drug)compound, which will eliminate the adjacent double bond. Therefore, drugcompounds having a keto group that may be ether linked to a halogenatedphenol ring of a starting compound of the present invention must have asingle bond adjacent to the keto carbon that is capable of forming adouble bond (usually by elimination of a bond to a hydrogen).Accordingly, an adjacent carbon of a drug compound may not be bonded tomore than three non-hydrogen atoms, and an adjacent nitrogen may not bebonded to more than two non-hydrogen atoms, so that they are able toaccept the double bond. According to some embodiments, for a drugcompound having a keto group to be ether linked to a halogenated phenolring such that the starting compound will reform the drug compound uponcleavage, the carbon of the keto group and the adjacent double bond maypreferentially be part of a six-membered ring structure having partialaromaticity (i.e., with one or two double bonds including the adjacentdouble bond). Without being bound by any theory, it is believed that insome cases, the electrons of the partially aromatic ring may assist informing the intermediate, which then resonates to form the lower energyketo-tautomer, although this may not always be necessary.

Due to the wide range of chemical groups that may be covalently linkedto a halogenated phenol ring, the general applicability of the presentinvention is potentially very broad. The range of drugs or compoundscontaining one or more of: a hydroxyl, keto, carboxyl, amino, alcohol,sulfonic acid or sulfhydryl group, or a hydrogen (—H) bonded to an“internal” nitrogen of a secondary amine compound, that may be linked toa halogenated phenol compound is very large. Indeed, these chemicalgroups or substituents are ubiquitously present in natural and syntheticcompounds. Thus, according to embodiments of the present invention, thecompound or drug linked or bonded to the halogenated phenol ring (andreleased during the cleavage reaction) may theoretically include a largevariety of drugs or compounds containing one or more of: a hydroxyl(—OH), keto (C═O), carboxyl (—COOH), amino (—NH₂), alcohol (—CH₂OH),sulfonic acid (SO₃H) or sulfhydryl (—SH) group(s), or a hydrogen (—H)bonded to an “internal” nitrogen in the case of a secondary aminecompound, that may be linked as described herein. To name a few,examples of drug compounds that may be linked to a halogenated phenolring as a part of a starting compound of the present invention mayinclude steroids, some of which may be anti-inflammatory steroidincluding corticosteroids, such as cortisol, cortisone, corticosterone,hydrocortisone, prednisone, prednisolone, methylprednisolone,betamethasone, etc., or other steroids, such as estrogen, etc., peptideand non-steroidal hormones, such as insulin, etc., thyroid hormones,such as thyroxine, triiodothyronine, etc., catecholamines, such asdopamine, L-DOPA, etc., adrenergics, such as epinephrine,norepinephrine, etc., amino acids, such as tyrosine, cysteine, serine,etc., antibiotics, such as β-lactam antibiotics including penicillins,cephalosporins, etc., anti-inflammatories, antipyretics, analgesics andNSAIDs, such as aspirin, acetaminophen, ibuprofen, naproxen, etc.,vitamins, such as vitamin A, vitamin E, etc., narcotics and opioids,such as methadone, morphine, amphetamine, etc., serotonergics, such asserotonin, etc., chemotherapies or cytotoxic drugs, such asmethotrexate, etc., and many others.

A person skilled in the art would be able to select compounds, as wellas drug compounds or their metabolites in the body, that contain atleast one of the suitable substituents: a hydroxyl (—OH), a keto (C═O),a sulfonic acid (—SO₃H), a carboxyl (—COOH), an amino (—NH₂), an alcohol(—CH₂OH) or a sulfhydryl (—SH) group(s), or a hydrogen (—H) bonded to an“internal” nitrogen of a secondary amine compound, based on their knownchemical structure. See, e.g., The Merck Index: an encyclopedia ofchemicals, drugs and biological, 14th Edition, Merck, WhitehouseStation, N J (2006); and Aldrich Structure Index, Aldrich ChemicalCompany (1996), the contents and disclosure of which are incorporated byreference, providing a long list of known chemical compounds from whichcandidate compounds having one or more of these substituent(s) may beidentified and selected for purposes of the present invention. Accordingto the principles described herein, the appropriate linkage between theselected (candidate) compound and a halogenated phenol ring may bedetermined based on the respective substituent, and the chemicalstructure or formula of the starting compound formed by such linkage maythen be further determined according to the principles of the presentinvention as provided herein. Although it would not be feasible to drawevery chemical structure covered by the present invention, enoughenabling description and examples are provided herein to determine thechemical structure of any starting compound of the present invention.

According to some embodiments, a compound that may be linked to ahalogenated phenol ring to form a starting compound of the presentinvention may include not only known or existing drug compounds, butalso their known and anticipated metabolites. Many drugs are chemicallyor enzymatically modified in hepatic and other tissues of the body.Indeed, many drugs have structures that anticipate these mechanisms toform the active compound after being taken or administered. Since a keyadvantage of the present invention is the formation or release of a drugcompound at a site of need, such as a site of inflammation or diseasehaving high FROS), the drug compound may not undergo such modificationat the site or release and formation and thus may be attached in itsactive form. However, a drug compound may alternatively be attached inits “pro-drug” form in some circumstances, especially if it can bereadily converted into its active form at the site where it is formed.

According to the principles of the present invention as describedherein, any such compound or drug compound known in the art andidentified as having: a hydroxyl (—OH), keto (C═O), carboxyl (—COOH),amino (—NH₂), alcohol (—CH₂OH) sulfonic acid (—SO₃H), or sulfhydryl(—SH) group(s) or substituent(s), or a hydrogen (—H) bonded to an“internal” nitrogen of a secondary amine compound, may potentially belinked to a halogenated phenol ring by modification of the respectivesubstituent. As described further herein, a hydroxyl group (or possiblya keto group) of a (drug) compound may be ether linked (—O—) to ahalogenated phenol ring, a sulfhydryl group of a (drug) compound may bethioether linked (—S—) to a halogenated phenol ring, a carboxyl groupmay be carbonyl linked (—[C═O]—) to a halogenated phenol ring, asulfonic acid group may be sulfinyl linked (—[S═O]—) to a halogenatedphenol ring, and an amino group may be nitrogen linked (—NH—) to ahalogenated phenol ring. Likewise, a hydrogen bonded to an “internal”nitrogen of a secondary amine (drug) compound may be internal nitrogenlinked to a halogenated phenol ring. In some circumstances, an alcoholsubstituent (—CH₂OH) of a (drug) compound may be linked to a halogenatedphenol ring by a cleavable C—C bond.

As discussed further below, (i) cleavage of an ether linkage willproduce a hydroxyl on the liberated (drug) compound (which may resonateinto a keto group depending on the identity of the compound), (ii)cleavage of a thioether bond will produce a sulfhydryl group on theliberated compound, (iii) cleavage of a nitrogen linkage will produce anamino group on the liberated compound, (iv) cleavage of a carbonyllinkage may generally produce a carboxyl group on the liberatedcompound, (v) cleavage of a sulfinyl linkage will generally produce asulfinic acid group, (vi) cleavage of an internal nitrogen linkage willgenerally produce a secondary amine group on the liberated compound, and(vii) cleavage of a C—C bond may generally produce an alcohol group onthe liberated compound if cleavage occurs. In these cases, the cleavagereaction will liberate the (drug) compound as a result of thedehalogenation reaction. Thus, starting compounds of the presentinvention may potentially include any suitable compound (or drugcompound) linked to a halogenated phenol ring by any of these cleavablelinkages via a suitable substituent on the linked compound.

Cleavage of an ether, thioether or nitrogen linkage will produce ahydroxyl (or keto), sulfhydryl, or amino group, respectively, on theliberated compound by the addition of a hydrogen (the keto grouppresumably forms by tautomerization of the initially formed hydroxyl).However, in the case of a carbonyl linkage or C—C bond, cleavage willproduce a carboxyl or alcohol group by addition of a hydroxyl group. Itis not clear why some cleavage reactions add only a hydrogen to theliberated compound, while other reactions result ultimately in theaddition of a hydroxyl, but the difference may derive from the presenceof a carbon in both cases involving a carbonyl linkage or C—C bond. Onetheory could be that, in the case of a cleaved carbonyl linkage, analdehyde (by addition of only a hydrogen) is first formed as anintermediate, which is then subsequently converted into the carboxylicacid by oxidation. However, examples showing the formation of an alcohol(—CH₂OH) upon cleavage of a C—C bond would seem to counter this theoryand suggest direct addition of the hydroxyl group in these cases.Moreover, cleavage of a sulfinyl linkage will produce a sulfonic acidgroup on the liberated compound by the addition of an oxygen atom and ahydroxyl, which presents another curious distinction for this linkageand substituent.

As mentioned above, a variety of drug compounds may be linked to ahalogenated phenol ring for targeted release and delivery at high FROSsites in body. The following list of examples of drug compounds areprovided with the possible types of linkages to a halogenated phenolring listed in parenthesis (not necessarily exhaustive): E=ether linkageat a hydroxyl group; T=thioether linkage; N=nitrogen linkage; C≡carbonyllinkage; IN=internal nitrogen linkage; Ek=ether linkage at a keto group.

Examples of chemotherapeutic agents that may be linked to a halogenatedphenol ring may include alkylating agents, such as nitrogen mustardsincluding chlorambucil (C), cyclophosphamide (IN), ifosfamide (IN), andmelphalan (C, N), nitrosureas including carmustine (IN), streptozocin(E, IN) and lomustine (IN), and triazines including dacarbazine (N) andtemozolomide (N); antimetabolites, such as 5-fluorouridine or 5-FU (Ek,IN), 6-mercaptopurine (IN, T), capecitabine (E, IN), cladribine (E, N),clofarabine (E, N), floxuridine (E, IN), fludarabine (N, E), gemcitabine(E, N), cytarabine (E, N), azacitadine (E, N), azathioprine (IN),doxifluridine (E, IN), hydroxyurea (N, E), methotrexate (N, C, IN, Ek),pemetrexed (N, C, IN, Ek), pentostatin (E, IN), thioguanine (N, IN, T);antitumor antibiotics, such as actinomycin (IN, N, Ek), bleomycin (E, N,IN), mitomycin (N, Ek), and anthracyclines including daunorubicin (E,N), doxorubicin (E, N), epirubicin (E, N), idarubicin (E, N),mitoxantrone (E, IN) and valrubicin (E, IN); topoisomerase inhibitors,such as etoposide (E), teniposide (E), tafluposide (Ek), topotecan (E),irinotecan (E); mitotic inhibitors, such as taxanes including paclitaxel(E, IN), docetaxel (E, IN), epothilones including ixabepilone (E, IN),vinka alkaloids including vinblastine (E, IN), vincristine (E, IN),vindesine (E, IN) and vinorelbine (E, IN), and estramustine (E);corticosteroids, such as dexamethasone (E, Ek); kinase inhibitors, suchas bortezomib (IN, Ek), erlotinib (IN), sunitinib (IN, Ek), gefitinib(IN), imatinib (IN, Ek) and vismodegib (IN, Ek); histone deacetylaseinhibitors, such as vorinostat (IN, Ek) and romidepsin (IN, Ek);retinoids, such as tretinoin (C), alitretinoin (C) and bexarotene (C);Pt-based agents, such as carboplatin (N), cisplatin (N) and oxaliplatin(N); and others, such as fulvestrant (E), exemestane (Ek), megestrolacetate (E), bicalutamide (E, IN), flutamide (Ek, IN), nilutamide (Ek,IN), leuprolide (E, IN) and goserelin (E, IN),

Examples of analgesics, NSAIDs and anesthetics that may be linked to ahalogenated phenol ring may include acetaminophen (E, IN); NSAIDs, suchas diclofenac (C, IN), diflunisal (C, E), etodolac (C), fenoprofen (C),flurbiprofen (C), ibuprofen (C), indomethacin (C), ketoprofen (C),ketorolac (C), meclofenamate (C, IN), mefenamic acid (C, IN), meloxicam(E, IN), nabumetone (Ek), naproxen (C), oxaprozin (C), phenylbutazone(Ek), piroxicam (E, IN), sulindac (C), tolmetin (C); Cox-2 inhibitors,such as celecoxib (N); narcotics, such as buprenorphine (E), butorphanol(E), codeine (E), dihydrocodeine (E), hydrocodone (Ek), hydromorphone(E), levorphanol (E), methadone (Ek), morphine (E), nalbuphine (E),oxycodone (E), oxymorphone (E), pentazocine (E), propoxyphene (Ek) andtapentadol (E); central analgesics, such as tramadol (E); andanesthetics, such as benzocaine (N), dibucaine (IN, Ek), and lidocaine(IN, Ek).

Examples of antibiotics that may be linked to a halogenated phenol ringmay include aminoglycosides, such as amikacin (E, N), gentamicin (E, N),kanamycin (E, N), neomycin (E, N), netilmicin (E, N), tobramycin (E, N)and paromomycin (E, N); ansamycins, such as geldanamycin (E, N) andherbimycin (N, Ek); carbacephems, such as loracarbef (C, N);carbapenems, such as ertapenem (C, E, IN), doripenem (C, E, N), imipenem(E, C, IN), cilastatin (C, N, IN) and meropenem (C, E, IN);cephalosporins, such as cefadroxil (E, N, C), cefazolin (C, IN),cefalotin (C, IN), cefalexin (C, N), cefaclor (C, N), cefamandole (C, E,IN), cefoxitin (C, N), cefprozil (C, N, E), cefuroxime (C, N), cefixime(C, N), cefdinir (C, N), cefditoren (C, N), cefoperazone (C, E),cefotaxime (C, N), cefpodoxime (C, N), ceftazidime (C, N), ceftibuten(C, N), ceftizoxime (C, N), ceftriaxone (C, N), cefepime (N),ceftaroline fosamil (C, IN, Ek) and ceftobiprole (C, N); glycopeptides,such as teicoplanin (E, N), vancomycin (E, N, C) and telavancin (E, N);lincosamides, such as clindamycin (E, IN) and lincomycin (E, IN);lipopeptides, such as daptomycin (C, N, E); macrolides, such asazithromycin (E), clarithromycin (E), dirithromycin (E), erythromycin(E), roxithromycin (E), troleandomycin (Ek), telithromycin (E),spectinomycin (E, IN) and spiramycin (E); monobactams, such as aztreonam(N, C, Ek); and nitrofurans, such as nitrofurantoin (Ek).

Further examples of antibiotics that may be linked to a halogenatedphenol ring may include penicillins; such as amoxicillin (E, N, C),ampicillin (C, N, Ek), azlocillin (C, IN, Ek), carbenicillin (C, IN,Ek), cloxacillin (C, IN, Ek), dicloxacillin (C, IN, Ek), flucloxacillin(C, IN, Ek), mezlocillin (C, IN, Ek), methicillin (C, IN, Ek), nafcillin(C, IN, Ek), oxacillin (C, IN, Ek), penicillin G (C, IN, Ek), penicillinV (C, IN, Ek), piperacillin (C, IN, Ek), temocillin (C, IN, Ek) andticarcillin (C, IN, Ek); polypeptides, such as bacitracin (C, N, Ek),colistin (E, N) and polymyxin b (N, E); quinolones, such asciprofloxacin (C, IN, Ek), enoxacin (C, IN), gatifloxacin (C, IN),levofloxacin (C), lomefloxacin (C, IN), moxifloxacin (C, IN), nalidixicacid (C), norfloxacin (C, IN), ofloxacin (C), trovafloxacin (C, N),grepafloxacin (C, IN), sparfloxacin (C, N) and temafloxacin (C, IN);sulfonamides, such as mafenide (N), sulfonamidochrysoidine (N),sulfacetamide (N), sulfadiazine (N), sulfamethizole (N),sulfamethoxazole (N), sulfanilimide (N), sulfasalazine (C, E) andsulfisoxazole (N); tetracyclines, such as demeclocycline (E, N),doxycycline (E, N), minocycline (E, N), oxytetracycline (E, N) andtetracycline (E, N); mycobacterial agents, such as clofazimine (IN),dapsone (N), capreomycin (N, E), cycloserine (N, Ek), ethambutol (E,IN), ethionamide (N), isoniazid (N, Ek), pyrazinamide (N, Ek),rifampicin (E, IN), rifabutin (E, IN), rifapentine (E, IN) andstreptomycin (E, N); and others, such as arsphenamine (E, N),chloramphenicol (E, IN), fusidic acid (C, E), linezolid (IN),metronidazole (E), mupirocin (C, E), platensimycin (E, C), rifaximin(E), thiamphenicol (E), tigecycline (N, E) and trimethoprim (N).

As mentioned above, one of the key advantages of present embodiments isthe targeted release of therapeutic compounds at sites of free radicalsand/or oxidative stress, which may reduce side effects in non-targetedtissues. Sites of infection or autoimmunity will generally be associatedwith inflammation and higher levels of FROS. For example, the targetedrelease of cortisone and antioxidants may occur in arthritic jointswhile minimizing systemic effects of the cortisone due to its maskingprior to release. As another example, an antibiotic may have targetedrelease preferentially at sites of infection, which may reduce unwantedside effects. Likewise, targeted release of neurotransmitters, perhapsin concert with antioxidants, within brain regions affected by damageand/or free radical/oxidative stress resulting from disease processes,such as Parkinson's or Alzheimer's diseases, may alter the course offurther neuro-degeneration in these brain regions. As a further example,targeted release of chemotherapeutic agents may be achieved at sites ofcancer or tumors, which may reduce side effects on normal or healthycells or tissues. Indeed, tumors may be hypermetabolic and elicit alocal inflammatory response, which may each lead to the release and/orleakage of FROS at these sites.

With regard to the targeted delivery of drugs, FIGS. 1-14 providegeneral formulas and examples of compounds or drugs that are ether (orthioether) linked to a halogenated phenol ring, which may be released bycleavage of the ether or thioether bond by the dehalogenation reaction.Later discussion in the text and figures will present examples for othertypes of chemical linkages introduced above (e.g., carbonyl linkage,etc.) that may be used in place of an ether or thioether linkage forthese embodiments.

FIG. 1 provides a general class of compounds (Formula 1) according toembodiments of the present invention. According to these embodiments, acompound (R₁—YH), such as a drug compound, may be bonded or linked by anether or thioether linkage to a halogenated phenol ring to form part ofa compound of the present invention. The ether or thioether linkage(—Y—) may be an ether linkage or group if Y is an oxygen atom and the—YH group is a hydroxyl group, or a thioether linkage or group if Y is asulfur atom and the —YH group is a sulfhydryl group. X is a halogen inthe ortho position relative to a hydroxyl group (—OH) on the phenol ring(i.e., X is a halogen that is bonded to a carbon that is adjacent to acarbon bonded to a hydroxyl group (—OH) on the phenol ring). The halogenX may be selected from either iodine (I) or bromine (Br), but generallymay not include fluorine (F) or chlorine (Cl). According to theseembodiments, the ether or thioether linkage (—Y—) is positioned in themeta position relative to the halogen X on the phenol ring and in thepara position relative to the hydroxyl group (—OH) on the phenol ring.The identity of each of the other substituents, R₂, R₃, and R₄, presenton the phenol ring may vary and may include, for example, a hydrogen, ahydroxyl, a sulfhydryl, an alkyl, a halogen, an amino, a nitro, etc.,groups. Unlike halogen X adjacent to the hydroxyl group of the phenolring, substituents R₂, R₃, and R₄ may be any halogen atom. According tosome alternative embodiments, one, two, or three of these variablesubstituents may be hydrogen. Furthermore, combinations of these othersubstituents, R₂, R₃, and R₄, present on the phenol ring may themselvesform fused rings with the halogenated phenol ring.

The substituents R₁—Y and R₂, R₃, and R₄ are each shown in FIG. 1 tobisect the bonds between carbons of the phenol ring as a standard andconventional depiction to represent that the actual positions of thosesubstituents may vary among the carbons of the ring in relation to eachother and in relation to the halogen (X) and the hydroxyl (OH) groups.This standard depiction is also used throughout this specification andaccompanying figures to represent variable positioning of substituents.By contrast, when a substituent is shown directly bonded to a carbon ofa ring structure, then that positioning is fixed. In addition, hydrogensthat are part of a chemical structure may or may not be shown. As iscustomary, when a substituent that must be present according to thechemical laws of valency is not shown, then it is hydrogen. Thus, if acarbon atom of a compound is shown with fewer than four bonds, then theremainder of the substituents on that carbon are hydrogen(s).

According to embodiments of the present invention shown in FIG. 1, whena compound of Formula 1 comes in contact with an oxidizing agent or freeradical or is present in an oxidizing and/or free radical containingenvironment, the halogen X is cleaved and removed from the phenol ringand replaced with a hydroxyl group. This free radical attack oroxidation of the phenol ring further results in the breaking or cleavageof the ether or thioether linkage (—Y—) between the drug compound andthe phenol ring to release the drug compound (R₁—YH), and the ether orthioether linkage is replaced by a hydroxyl group on the phenol ring.The origin of the two hydroxyls replacing the halogen and the formerether (or thioether) linkage on the phenol ring is presumably from thewater molecules of the surrounding aqueous environment, and the hydrogenadded to the oxygen or sulfur atom (Y) on the liberated drug compound isalso presumably from the aqueous environment. In addition to release ofa proton (H⁺; not shown), a halide (X⁻) and drug compound, abenzenetriol-based or hydroxyhydroquinone-based compound (e.g.,1,2,4-benzenetriol) may be formed. However, the exact formula name forthis product of the reaction will depend on the identity of theadditional substituents, R₂, R₃, and R₄. Indeed, one or more of theseadditional substituents may be hydroxyl groups.

FIG. 2 provides a general class of compounds (Formula 2) according toembodiments of the present invention. According to these embodiments, acompound (R₁—YH), such as a drug compound, may be bonded or linked by anether or thioether linkage to a halogenated phenol ring to form part ofa compound of the present invention. The ether or thioether linkage(—Y—) may be an ether linkage if Y is an oxygen atom and the —YH groupis a hydroxyl group, or a thioether linkage if Y is a sulfur atom andthe —YH group is a sulfhydryl group. X is a halogen in the orthoposition relative to the hydroxyl group (—OH) on the phenol ring (i.e.,X is a halogen that is bonded to a carbon that is adjacent to a carbonbonded to the hydroxyl group (—OH) on the phenol ring). The halogen Xmay be selected from either iodine (I) or bromine (Br), but generallymay not include fluorine (F) or chlorine (Cl). According to theseembodiments, the ether or thioether linkage (—Y—) is positioned in thepara position relative to the halogen X on the phenol ring and in themeta position relative to the hydroxyl group (—OH) on the phenol ring.The identity of each of the other substituents, R₂, R₃, and R₄, presenton the phenol ring may vary and may include, for example, a hydrogen, ahydroxyl, a sulfhydryl, an alkyl, a halogen, an amino, a nitro, etc.,groups. Unlike halogen X adjacent to the hydroxyl group of the phenolring, substituents R₂, R₃, and R₄ may be any halogen atom. According tosome alternative embodiments, one, two, or three of these variablesubstituents may be hydrogen. Furthermore, combinations of these othersubstituents, R₂, R₃, and R₄, present on the phenol ring may themselvesform fused rings with the halogenated phenol ring.

According to these embodiments in FIG. 2, when a compound of Formula 2comes in contact with an oxidizing agent or free radical or is presentin an oxidizing and/or free radical containing environment, the halogenX is cleaved and removed from the phenol ring and replaced with ahydroxyl group. This free radical attack or oxidation of the phenol ringfurther results in the breaking or cleavage of the ether or thioetherlinkage (—Y—) between the drug compound and the phenol ring to releasethe drug compound (R₁—YH), and the ether or thioether linkage isreplaced by a hydroxyl group on the phenol ring. In addition to releaseof a proton (H⁺; not shown), a halide (X⁻) and drug compound, abenzenetriol-based or hydroxyhydroquinone-based compound (e.g.,1,2,4-benzenetriol) may be formed. However, the exact formula name forthis product of the reaction will depend on the identity of theadditional substituents, R₂, R₃, and R₄. Indeed, one or more of theseadditional substituents may be hydroxyl groups.

FIG. 3 provides a general class of compounds (Formula 3) according toembodiments of the present invention. According to these embodiments, acompound (R₁—YH), such as a drug compound, may be bonded or linked by anether or thioether linkage to a halogenated phenol ring to form part ofa compound of the present invention. The ether or thioether linkage(—Y—) may be an ether linkage if Y is an oxygen atom and the —YH groupis a hydroxyl group or a thioether linkage or group if Y is a sulfuratom and the —YH group is a sulfhydryl group. X is a halogen in theortho position relative to the hydroxyl group (—OH) on the phenol ring(i.e., X is a halogen that is bonded to a carbon that is adjacent to acarbon bonded to the hydroxyl group (—OH) on the phenol ring). Thehalogen X may be selected from either iodine (I) or bromine (Br), butgenerally may not include fluorine (F) or chlorine (Cl). According tothese embodiments, the ether or thioether linkage (—Y—) is positioned inthe meta position relative to the halogen X on the phenol ring and inthe ortho position relative to the hydroxyl group (—OH) on the phenolring. The identity of each of the other substituents, R₂, R₃, and R₄,present on the phenol ring may vary and may include, for example, ahydrogen, a hydroxyl, a sulfhydryl, an alkyl, a halogen, an amino, anitro, etc., groups. Unlike halogen X adjacent to the hydroxyl group ofthe phenol ring, substituents R₂, R₃, and R₄ may be any halogen atom.According to some alternative embodiments, one, two, or three of thesevariable substituents may be hydrogen. Furthermore, combinations ofthese other substituents, R₂, R₃, and R₄, present on the phenol ring maythemselves form fused rings with the halogenated phenol ring.

According to these embodiments in FIG. 3, when a compound of Formula 3comes in contact with an oxidizing agent or free radical or is presentin an oxidizing and/or free radical containing environment, the halogenX is cleaved and removed from the phenol ring and replaced with ahydroxyl group. This free radical attack or oxidation of the phenol ringfurther results in the breaking or cleavage of the ether or thioetherlinkage (—Y—) between the drug compound and the phenol ring to releasethe drug compound (R₁—YH), and the ether or thioether linkage isreplaced by a hydroxyl group on the phenol ring. In addition to releaseof a proton (H⁺; not shown), a halide (X⁻) and drug compound, abenzenetriol-based compound (e.g., 1,2,3-benzenetriol or pyrogallol) maybe formed. However, the exact formula name for this product of thereaction will depend on the identity of additional substituents, R₂, R₃,and R₄.

FIG. 4 provides a general class of compounds (Formula 4) according toembodiments of the present invention. According to these embodiments, acompound (R₁—YH), such as a drug compound, may be bonded or linked by anether or thioether linkage to a halogenated phenol ring to form part ofa compound of the present invention. The ether or thioether linkage(—Y—) may be an ether linkage if Y is an oxygen atom and the —YH groupis a hydroxyl group or a thioether linkage if Y is a sulfur atom and the—YH group is a sulfhydryl group. X is a halogen in the ortho positionrelative to the hydroxyl group (—OH) on the phenol ring (i.e., X is ahalogen that is bonded to a carbon that is adjacent to a carbon bondedto the hydroxyl group (—OH) on the phenol ring). The halogen X may beselected from either iodine (I) or bromine (Br), but generally may notinclude fluorine (F) or chlorine (Cl). According to these embodiments,the ether or thioether linkage (—Y—) is positioned in the ortho positionrelative to the halogen X on the phenol ring and in the meta positionrelative to the hydroxyl group (—OH) on the phenol ring. The identity ofeach of the other substituents, R₂, R₃, and R₄, present on the phenolring may vary and may include, for example, a hydrogen, a hydroxyl, asulfhydryl, an alkyl, a halogen, an amino, a nitro, etc., groups. Unlikehalogen X adjacent to the hydroxyl group of the phenol ring,substituents R₂, R₃, and R₄ may be any halogen atom. According to somealternative embodiments, one, two, or three of these variablesubstituents may be hydrogen. Furthermore, combinations of these othersubstituents, R₂, R₃, and R₄, present on the phenol ring may themselvesform fused rings with the halogenated phenol ring.

According to these embodiments in FIG. 4, when a compound of Formula 4comes in contact with an oxidizing agent or free radical or is presentin an oxidizing and/or free radical containing environment, the halogenX is cleaved and removed from the phenol ring and replaced with ahydroxyl group. This free radical attack or oxidation of the phenol ringfurther results in the breaking or cleavage of the ether or thioetherlinkage (—Y—) between the drug compound and the phenol ring to releasethe drug compound (R₁—YH), and the ether or thioether linkage isreplaced by a hydroxyl group on the phenol ring. In addition to releaseof a proton (H⁺; not shown), a halide (X⁻) and drug compound, abenzenetriol-based compound (e.g., 1,2,3-benzenetriol or pyrogallol) maybe formed. However, the exact formula name for this product of thereaction will depend on the identity of additional substituents, R₂, R₃,and R₄.

According to embodiments of the present invention, two or morecompounds, such as drug compounds, may be bonded or linked by an etheror thioether linkage to the same halogenated phenol ring. According tothese embodiments, two or more compounds may be concertedly orsimultaneously (or nearly simultaneously) released upon exposure of thehalogenated phenol ring to free radicals and/or oxidizing agents. In thecase of drug compounds, such an approach may have utility forco-administering two or more drug compounds to a site of disease orinflammation within the body of an individual as part of a combinedtherapy, for example when simultaneous exposure of a tissue, cells,tissue/cell environment, infectious agent, etc., at the site of diseaseor inflammation to the two or more drug compounds has a particularbenefit or synergistic effect compared to the separate taking oradministration of the drug compounds.

FIG. 5 provides a general class of compounds (Formula 5) according toembodiments of the present invention. According to these embodiments,two compounds (R₁—Y₁H and R₂—Y₂H), such as two drug compounds, may eachbe bonded or linked by an ether or thioether linkage to a halogenatedphenol ring to form parts of a compound of the present invention. Theether or thioether linkages (—Y₁— and —Y₂—) may each be an ether linkageif Y₁ or Y₂ is an oxygen atom and the —Y₁H group or the —Y₂H group is ahydroxyl group, or a thioether linkage if Y₁ or Y₂ is a sulfur atom andthe —Y₁H group or the —Y₂H group is a sulfhydryl group. X is a halogenin the ortho position relative to the hydroxyl group (—OH) on the phenolring (i.e., X is a halogen that is bonded to a carbon that is adjacentto a carbon bonded to the hydroxyl group (—OH) on the phenol ring). Thehalogen X may be selected from either iodine (I) or bromine (Br), butgenerally may not include fluorine (F) or chlorine (Cl).

According to these embodiments, the ether or thioether linkages (—Y₁—and —Y₂—) may be positioned anywhere on the phenol ring not occupied bythe ortho-positioned hydroxyl group and halogen (X) (i.e., on any of theremaining carbons of the phenol ring). Similarly, additionalsubstituents R₃ and R₄ may be positioned anywhere on the phenol ring notoccupied by the ortho-positioned hydroxyl group and halogen (X) (i.e.,on any of the remaining carbons of the phenol ring). The identity ofeach of the additional substituents, R₃ and R₄, present on the phenolring may vary and may include, for example, a hydrogen, a hydroxyl, asulfhydryl, an alkyl, a halogen, an amino, a nitro, etc., groups. Unlikehalogen X adjacent to the hydroxyl group of the phenol ring,substituents R₃ and R₄ may be any halogen atom. According to somealternative embodiments, one or both of these variable substituents maybe hydrogen. Furthermore, substituents R₃ and R₄ may together form afused ring with the halogenated phenol ring. In all of the figures, thedrawing of a bond line between carbons of a benzene or phenol ring meansthat such a bond may involve (i.e., be bonded to) any of the remainingcarbons of the ring (in the alternative) that are not fixedly orotherwise occupied or bonded to another substituent or group.

According to embodiments of the present invention in FIG. 5, when acompound of Formula 5 comes in contact with an oxidizing agent or freeradical or is present in an oxidizing and/or free radical containingenvironment, the halogen (X) is cleaved and removed from the phenol ringand replaced with a hydroxyl group. This free radical attack oroxidation of the phenol ring further results in the breaking or cleavageof the ether or thioether linkages (—Y₁— and —Y₂—) between the drugcompound and the phenol ring to release the drug compounds (R₁—Y₁H andR₂—Y₂H), and each of the ether or thioether linkages is replaced by ahydroxyl group on the phenol ring. In addition to release of a halide(X⁻) and drug compounds, a benzenetetrol-based compound (e.g.,1,2,3,4-benzenetetrol, 1,2,3,5-benzenetetrol, or 1,2,4,5-benzenetetrol)may be formed. However, the exact formula name for this product of thereaction will depend on the identity of the additional substituents, R₃and R₄.

According to embodiments of the present invention, two or morecompounds, such as drug compounds, may be bonded or linked by an etheror thioether linkage to two or more halogenated phenol rings. Accordingto these embodiments, two or more compounds may be released in asequential fashion upon exposure of the halogenated phenol rings to freeradicals and/or oxidizing agents. In the case of drug compounds, such anapproach may have utility for delivering or co-administering two or moredrug compounds to a site of disease or inflammation within the body ofan individual as part of a combined therapy, especially when an orderedor sequential exposure of a tissue, cells, tissue or cell environment,infectious agent, etc., at the site of disease or inflammation to thetwo or more drug compounds has a particular benefit or synergisticeffect compared to the separate taking or administration of the drugcompounds. Such an approach may be useful as an alternative totreatments involving multivalent treatments or cocktails of drugs andfor synergistic or complementary drug combinations. There may also be anadvantage to attaching drug compounds to two or more ether or thioetherlinked halogenated phenol rings. For example, there may be an advantageto attaching drug compounds to two or more ether or thioether linkedhalogenated phenol rings to improve chemical synthesis (e.g., toovercome steric hindrance if the two drug compounds are attached to thesame phenol ring) or reactive properties. Release of a first drugcompound may have a particular effect that improves the subsequentimpact of a second drug compound at the site. For example, release ofthe first drug compound may render the target of the drug compounds(e.g., tissue, cells, tissue or cell environment, infectious agents,etc.) at the site of disease or inflammation more vulnerable,susceptible or sensitive to treatment by the second compound.

FIG. 6A provides a general class of compounds (Formula 6) according toembodiments of the present invention. According to these embodiments,two conjugated compounds, such as two drug compounds, consisting of afirst compound (R₁—Y₁H) and a second compound (R₂—Y₂H), may each bebonded or conjugated by ether or thioether linkage to two halogenatedphenol rings including a first phenol ring and a second phenol ring,with the first phenol ring and the second phenol ring linked together byan ether (—O—) linkage. The first compound (R₁—Y₁H) is bonded by anether or thioether linkage to the first phenol ring, and the secondcompound (R₂—Y₂H) is bonded by an ether or thioether linkage to a secondphenol ring, such that the first and second compounds form part of thecompound of the present invention. Ether or thioether linkage (—Y₁—) onthe first phenol ring may be either an ether linkage if Y₁ is an oxygenatom and the —Y₁H group is a hydroxyl group or a thioether linkage if Y₁is a sulfur atom and the —Y₁H group is a sulfhydryl group. Ether orthioether linkage (—Y₂—) on the second phenol ring may be either anether linkage if Y₂ is an oxygen atom and the —Y₂H group is a hydroxylgroup or a thioether linkage if Y₂ is a sulfur atom and the —Y₂H groupis a sulfhydryl group.

According to these embodiments in FIG. 6A, substituents X₁ and X₂ ofFormula 6 are each halogens present on the first and second phenolrings, respectively, with each halogen X₁ and X₂ in the ortho positionrelative to either the hydroxyl group (—OH) on the first phenol ring orthe ether linkage on the second phenol ring (i.e., X₁ is a halogenbonded to a carbon of the first phenol ring that is adjacent to a carbonof the first phenol ring that is bonded to the hydroxyl group, and X₂ isa halogen bonded to a carbon of the second phenol ring that is adjacentto a carbon of the second phenol ring that is linked by an ether linkageto the first phenol ring). Each of the halogens X₁ and X₂ may be eitheriodine (I) or bromine (Br), but generally may not include fluorine (F)or chlorine (Cl).

According to these embodiments in FIG. 6A, ether or thioether linkage(—Y₁—) as well as additional substituents R₃ and R₄ may each bepositioned on any of the remaining three carbons of the first phenolring that are not occupied by the ortho-positioned hydroxyl group (—OH)and halogen X₁ or by the ether linkage connecting the first and secondphenol ring. Ether or thioether linkage (—Y₂—) as well as additionalsubstituents R₅, R₆, and R₇ may each be positioned on any of theremaining four carbons of the second phenol ring that is not occupied bythe halogen X₂ or by the ether linkage connecting the first and secondphenol ring. The identity of each of the additional substituents, R₃,R₄, R₅, R₆, and R₇ may vary and may include, for example, a hydrogen, ahydroxyl, a sulfhydryl, an alkyl, a halogen, an amino, a nitro, etc.,groups. Unlike halogens X₁ or X₂, substituents R₃, R₄, R₅, R₆, and R₇may be any halogen atom. According to some alternative embodiments, one,two, three, four or five of these variable substituents may be hydrogen.Furthermore, any combination of substituents R₃ and R₄ and/or anycombination of substituents R₅, R₆, and R₇ may together form a fusedring with their respective halogenated phenol ring.

According to embodiments of the present invention, when a compound ofFormula 6 comes in contact with an oxidizing agent or free radical or ispresent in an oxidizing and/or free radical containing environment, thehalogen X₁ of the first phenol ring may be cleaved from the first phenolring and replaced with a hydroxyl group. This free radical attack oroxidation of the first phenol ring may further result in the breaking orcleavage of the ether linkage (—O—) between the first and second phenolrings and the ether or thioether linkage (—Y₁—) to release the firstdrug compound R₁—Y₁H and the second phenol ring from the first phenolring. Both the ether linkage (—O—) between the first and second phenolrings and the ether or thioether linkage (—Y₁—) between the first phenolring and the first drug compound are replaced on the first phenol ringby a hydroxyl group. In addition to the release of a halide (X₁ ⁻),first drug compound, and second phenol ring, a benzenetetrol-basedcompound (e.g., 1,2,3,4-benzenetetrol, 1,2,3,5-benzenetetrol, or1,2,4,5-benzenetetrol) may be formed. However, the exact formula namefor this product will depend on the identity of the additionalsubstituents, R₃ and R₄. As a product of this reaction, the second drugcompound will remain bonded to the second phenol ring via the secondether or thioether linkage (—Y₂—), and the ether linkage (—O—) betweenthe first and second phenol rings will also be replaced by a hydroxylgroup on the second phenol ring as shown in Formula 7.

According to the embodiments shown in FIG. 6A, one of the products ofthe reaction is the second phenol ring bonded to the second drugcompound (Formula 7). The second drug compound may then be released in asecond chemical event when a compound of Formula 7 comes in contact withan oxidizing agent or free radical, or is present in an oxidizing and/orfree radical containing environment. Therefore, a compound of Formula 6has the effect of releasing a first drug compound and a second drugcompound sequentially in time with the first drug compound beingreleased during a first chemical event triggered by an oxidizing agentor free radical and the second drug compound being released subsequentlyduring a second chemical event triggered by another oxidizing agent orfree radical.

According to the embodiments shown in FIG. 6B, when a compound ofFormula 7 comes in contact with an oxidizing agent or free radical, thehalogen X₂ of the second phenol ring is cleaved from the second phenolring and replaced with a hydroxyl group. This free radical attack oroxidation of the second phenol ring further results in the breaking orcleavage of the ether or thioether linkage (—Y₂—) between the secondphenol ring and the second drug compound to release the second drugcompound R₂—Y₂H from the second phenol ring, and the ether or thioetherlinkage (—Y₂—) is replaced by a hydroxyl group on the second phenolring. In addition to the release of a halide (X₂ ⁻) and second drugcompound, a benzenetriol-based or hydroxyhydroquinone-based compound(e.g., 1,2,4-benzenetriol or 1,2,3-benzenetriol) may be formed. However,the exact formula name for this product will depend on the identity ofthe additional substituents, R₅, R₆, and R₇.

As supported by the general classes of compounds in FIGS. 6A and 6B,embodiments of the present invention may potentially include polymers ofhalogenated phenol ring units of any length with each unit of thepolymer ether or thioether linked to a drug compound and linked to itsneighboring unit(s) of the polymer by an ether linkage. As shownconceptually in FIG. 7, drug compounds may be released sequentially (oneat a time) through successive reaction events or steps triggered byexposure of the polymer to oxidizing agents and/or free radicals. Drugcompounds are shown in FIG. 7 bonded to each of the units of thepolymer. These drug compounds, which form part of the polymer compoundof the present invention, are released sequentially to yield a polymerof shorter length along with a benzenetetrol- or benzenetriol-basedproduct and a halide (X⁻). Although the other substituents on each unitof the polymer shown in FIG. 7 are depicted as being hydrogens, theseother substituents may also vary similarly as shown described above inreference to FIG. 6 and Formula 6 therein. As an alternative to thegeneral class of formulas encompassed by FIGS. 6 and 7, the ether orthioether linkages may instead be replaced with the other types oflinkages (e.g., carbonyl linkage, etc.) as described further herein withthe other substituents of these formulas possibly remaining the same.

According to embodiments of the present invention, any combination ofthe same, similar, or different drug compounds may be bonded to theunits of the polymer. According to some embodiments, not all units of apolymer need to be bonded (i.e., ether or thioether linked) to acompound, such as a drug compound. These “empty” units of the polymermay be used to create a desired spacing between units bonded to one ormore compound(s) or drug compound(s) to achieve a preferred timing orsustained release of the compound(s) or drug compound(s). For example,the number of “empty” polymer units ahead of unit(s) bonded to drugcompound(s) may be used to engineer the timing or delay of release forthe drug compound(s) after its initial administration to an individual,or alternatively, the spacing between units of a polymer bonded to drugcompound(s) may be used to engineer the relative timing of release fortwo or more drug compounds. Polymer compounds according to theseembodiments may range greatly in size and may include polymers of 2-200units in length, or alternatively polymers of 2-100 units, 2-50 units,2-25 units, 2-10 units, or 2-5 units in length, but longer polymers arealso possible. According to some embodiments, the polymers may have aminimum of three (3) units in a range having the same upper limits.Likewise, the amount of spacing or number of “empty” units may varywidely and may include continuous lengths of 1-100, 1-50, 1-10, etc.,but longer spacings or lengths of empty units may also be used. Thenumber of middle units (n) may correspond to these total lengths.According to FIG. 7, if the total number of units (i.e., total length)is two (2), then n would equal zero (0). If the total number of unitswas three (3), then n would equal one (1), and so on.

Another advantage of these embodiments of the present invention is thatby combining one or more drug compound(s) on the same molecule, polymeror chain, such as in FIGS. 5-7, the relative amounts of the drugcompound(s) on the molecule may be controlled, and the relative amountsof these drugs formed or liberated by the dehalogenation reaction andthus delivered to high FROS target tissues may be controlledstoichiometrically.

According to embodiments of the present invention, such as thosepresented in the figures above, the identity and position ofsubstituents on the halogentated phenol ring including, for example, thehalogen (X) at the ortho position of the phenol ring relative to thehydroxyl group as well as the additional substituents R₂, R₃, etc., maybe chosen to achieve desired characteristics. For example, the identityand position of substituents on the halogentated phenol ring may bechosen to adjust the sensitivity with which the linkage (e.g., etherlinkage, etc.) between a phenol ring and a (drug) compound is broken orcleaved in response to free radicals or oxidative agents. Without beingbound by theory, it is believed that stabilizing the phenol ring willgenerally result in lowering the sensitivity of cleavage and raising thethreshold for cleavage and release of a drug compound. Generallyspeaking, it is believed that increasing the number and/or strength ofelectron withdrawing groups on the phenol ring of a halogenated phenolcompound may result in destabilizing the phenol ring, while increasingthe number and/or strength of electron donating groups on the phenolring of a halogenated phenol compound may result in stabilizing thephenol ring. For example, increasing the number of halogen substituentsmay destabilize the phenol ring and lower the threshold (i.e., increasethe sensitivity) for cleavage of the ether or thioether linkage andrelease of a drug compound. Using bromine (Br) for the halogen (X) ofthe phenol ring at the ortho position relative to the hydroxyl group mayhave the effect of stabilizing the halogenated phenol ring (thus raisingthe threshold and lowering the sensitivity) compared to iodine (I).Other possibilities include the use of amino groups, which maydestabilize the ring and lower the threshold of sensitivity, or the useof nitro groups, which may stabilize the ring and raise the threshold ofsensitivity. Also, as stated above, linking the (drug) compound at thepara position relative to the hydroxyl group on the halogenated phenolring may result in a higher sensitivity of cleavage relative to linkagesat the meta and ortho positions.

Although these principles are proposed as possible bases for modifyingor designing the sensitivity of cleavage for a halogenated phenolcompound in response to free radicals or oxidative stress, the preciseeffects of any given substituent on the sensitivity of cleavage for aparticular halogenated phenol compound may depend greatly on the fullchemical formula of the halogenated phenol compound and thecircumstances under which the compound is used. To determine thesensitivity of cleavage directly for a particular halogenated phenolcompound, empirical or trial-and-error methods may be used. For example,the amount of detectable product(s) (e.g., including quinone products orhalides) of the reaction may be measured in vitro under controlledconditions to determine the sensitivity of cleavage for a givenhalogenated phenol compound.

FIG. 8A shows an example embodiment of the present invention for a3-hydroxy-3′-iodo-L-thyronamine or1-ethylamine-3-hydroxy-3′-iodo-4′-hydroxy-diphenyl ether compound(Compound 8) that may be converted into a 3-hydroxytyramine compound(i.e., dopamine). According to this embodiment, when Compound 8 comes incontact with an oxidizing agent or free radical, or is present in anoxidizing and/or free radical containing environment, the iodine (I) ofthe outer phenol ring is cleaved and replaced with a hydroxyl group.This free radical attack or oxidation of the outer phenol ring furtherresults in the breaking or cleavage of the ether linkage (—O—) betweenthe inner and outer phenol rings to release the dopamine drug compound.In addition to the release of dopamine and an iodide (F), abenzenetriol-based compound (e.g., 1,2,4-benzenetriol or1,2,3-benzenetriol) is formed. Formation of dopamine in the brain may beeffective in treating brain disorders, such as Parkinson's disease.

As another alternative shown in FIG. 8B, a starting compound may be a3-hydroxy-3′-iodo-L-thyronine compound that may be used to release a3,4-dihydroxy compound (i.e., L-DOPA) in FROS-containing tissue. TheL-DOPA product of this reaction may then be further converted intodopamine via the activity of a DOPA decarboxylase enzyme present in atargeted tissue where the L-DOPA compound is formed. According toanother similar embodiment, the outer phenol ring may comprise two ormore iodine (or other halogen) atoms instead of one. For example, thestarting compound may be a 3-hydroxy-3′,5′-diiodo-thyronine compound.

FIG. 9 shows an example embodiment of the present invention for aniodo-phenol compound linked by an ether linkage to an Estradiol drug toform part of the compound (Compound 9). According to this embodiment,when the Estradiol-linked iodo-phenol compound comes in contact with anoxidizing agent or free radical, or is present in an oxidizing and/orfree radical containing environment, the iodine (I) of the phenol ringis cleaved and replaced with a hydroxyl group. This free radical attackor oxidation of the phenol ring further results in the breaking orcleavage of the ether linkage (—O—) between the phenol ring and theEstradiol drug compound to release the Estradiol drug compound. Inaddition to the release of Estradiol and an iodide (I⁻), abenzenetriol-based or hydroxyhydroquinone-based compound (e.g.,1,2,4-benzenetriol or 1,2,3-benzenetriol) is formed.

FIG. 10 shows an example embodiment of the present invention for aniodo-phenol compound linked by an ether linkage to serotonin to formpart of the compound (Compound 10). As an alternative to Compound 10,this serotonin-releasing compound may be 3,5-diiodo-4-hydroxy-(N-acetyltryptamine)-1,5′-diphenyl ether. According to this embodiment, when theserotonin-linked iodo-phenol compound comes in contact with an oxidizingagent or free radical, or is present in an oxidizing and/or free radicalcontaining environment, the iodine (I) of the phenol ring is cleaved andreplaced with a hydroxyl group. This free radical attack or oxidation ofthe phenol ring further results in the breaking or cleavage of the etherlinkage (—O—) between the phenol ring and the serotonin drug compound torelease the serotonin drug compound. In addition to the release ofserotonin and an iodide (I⁻), a benzenetriol-based orhydroxyhydroquinone-based compound (e.g., 1,2,4-benzenetriol or1,2,3-benzenetriol) is formed.

FIG. 11 shows some additional examples of starting compounds that may beused to form common drug compounds as a result of the dehalogenation andcleavage reaction. FIG. 11A shows a drug, acetaminophen, ether linked toa halogenated phenol ring. Upon cleavage in the presence of FROS,acetaminophen is formed along with a 1,2,4-benzenetriol and a halide.FIG. 11B shows another drug, dihydromorphinone or DILAUDID®, etherlinked to a halogenated phenol ring. Upon cleavage in the presence ofFROS, the dihydromorphinone is formed along with a 1,2,4-benzenetrioland a halide. FIG. 11C shows yet another drug, morphine, ether linked toa halogenated phenol ring. Upon cleavage in the presence of FROS,morphine is formed along with a 1,2,4-benzenetriol and a halide. Thesecompounds may be useful in treating specific sites of inflammation,injury, infection or disease that may be associated with pain ordiscomfort by targeted delivery of the analgesic.

FIG. 12 shows an example embodiment of the present invention for aniodo-phenol compound linked by a thioether linkage to the amino acidcysteine to form part of the compound (Compound 12). This example isprovided in part as an example to demonstrate how molecules containing asulfhydryl group may be linked to a halogenated phenol group by athioether linkage according to embodiments of the present invention.According to this example, when the cysteine-linked iodo-phenol compoundcomes in contact with an oxidizing agent or free radical, or is presentin an oxidizing and/or free radical containing environment, the iodine(I) of the phenol ring is cleaved and replaced with a hydroxyl group.This free radical attack or oxidation of the phenol ring further resultsin the breaking or cleavage of the thioether linkage (—S—) between thephenol ring and cysteine to release the cysteine molecule. In additionto the release of the amino acid cysteine and an iodide (I⁻), abenzenetriol-based or hydroxyhydroquinone-based compound (e.g.,1,2,4-benzenetriol or 1,2,3-benzenetriol) is also formed.

FIG. 13 shows yet another example embodiment of the present inventionfor an iodo-phenol compound linked by an ether linkage to a moleculeresembling cortisone, which forms part of the starting compound(Compound 13). This example is provided in part to demonstrate howmolecules may be designed based on predictions about changes that mayoccur spontaneously or chemically in the arrangement of bonds and/orside groups of compounds that are ether linked to a halogenated phenolring once such a compound is released as a result of the dehalogenationand cleavage reaction. This example shows how a compound, such as a drugcompound, having a keto group and an adjacent double bond may be linkedto a halogenated phenol ring by an ether linkage to take advantage of atautomeric shift of a hydroxyl to form the keto group.

According to this example in FIG. 13, when Compound 13 comes in contactwith an oxidizing agent or free radical, or is present in an oxidizingand/or free radical containing environment, the iodine (I) of the phenolring is cleaved and replaced with a hydroxyl group. This free radicalattack or oxidation of the phenol ring further results in the breakingor cleavage of the ether linkage (—O—) between the phenol ring and thecortisone-like molecule to release the cortisone-like intermediatemolecule. In addition, an iodide (I⁻), a benzenetriol-based compound(i.e., 1,2,4-benzenetriol) is formed. However, to achieve a lower energystate, this cortisone-like intermediate molecule may then spontaneouslyundergo a further conversion by tautomerization to become a cortisonemolecule in the targeted tissue where the cortisone-like intermediate isformed.

Localized or targeted cortisone release may be useful in treating sitesof inflammation, such as arthritis, multiple sclerosis (MS), ischemicbowel disease, or other diseases associated with high levels of freeradical or oxidative species (FROS). Cortisone is a glucocorticoid withpotent anti-inflammatory activity, but it also causes undesired systemicside effects in non-target tissues that are not inflamed. Coupling ofcortisone to the halogenated phenol ring via a linkage, such as an etherlinkage, provides a bulky substitution that sterically blocks cortisoneactivity prior to release (and activation) by cleavage. Thus, thehalogenated phenol-linked product allows targeted delivery of theproduct to the inflamed site. Oxidative dehalogenation, with concertedcleavage of the linkage (e.g., the ether linkage) produces a transient3-hydroxy-cortisone at the site, which spontaneously converts orresonates to the 3-keto parent cortisone. As such, this mechanismprovides concentrated delivery of cortisone to the inflamed site.

Another example embodiment of a drug compound containing a keto groupthat is ether linked to a halogenated phenol ring to form a startingcompound (Compound 14) of the present invention is shown in FIG. 14. Thedrug compound in this example is a 5-iodo-uracil that may be used forthe treatment of cancer. When Compound 13 comes in contact with anoxidizing agent or free radical, or is present in an oxidizing and/orfree radical containing environment, one of the iodines (I) of thephenol ring adjacent to the hydroxyl group is cleaved and is replacedwith a hydroxyl group. This free radical attack or oxidation of thephenol ring further results in the breaking or cleavage of the etherlinkage (—O—) between the phenol ring and the core structure of the drugcompound, thus releasing an intermediate with a hydroxyl group in placeof a keto group (not shown). In addition, an iodide (I⁻), abenzenetriol-based compound (i.e., iodo-benzenetriol) is formed.However, to achieve a lower energy state, this intermediate may thenspontaneously undergo keto-enol transition or tautomerization to becomethe 5-iodo-uracil molecule in the targeted tissue where formed.

As with other chemotherapeutic drugs linked to a halogenated phenolring, Compound 14 may be delivered selectively to a targeted, high-FROStissue (e.g., a cancerous tissue or tumor), which may help to reduceside effects on normal tissue. Compound 14 consists of 5-iodo-uracil(5-IU) ether linked to the halogenated phenol ring at the site of one ofits keto groups. A similar compound, 5-fluoro-uracil (5-FU), iscurrently used as a chemotherapy agent. Indeed, 5-FU may also be a drugcompound linked to a halogenated phenol ring as part of startingcompound of the present invention. However, 5-iodo-uracil is less stablethan 5-FU and can form 5-hydroxy-uracil at some rate through spontaneousdeiodination. The 5-hydroxy-uracil product is cytotoxic and notpreferred due to its side effects on normal tissue. However, accordingto embodiments of the present invention, masking by the linkedhalogenated phenol ring results in delivery and release at the targetedsite. Thus, Compound 14 may be used to form 5-IU despite thecytotoxicity of its downstream 5-hydroxy-uracil product due to itsselective formation in the targeted tissue. In fact, the greater potencyof the 5-hydroxy-uracil product in conjunction with its targeteddelivery may prove more efficacious at treating these sites. Thisexample highlights another possible advantage of the present invention.Drug compounds that may have been previously considered to be toocytotoxic and/or produce too many unwanted side effects may be usedaccording to the present invention due to their masking by thehalogenated phenol ring and their targeted delivery to desired sites oftreatment. Another advantage discussed elsewhere herein is that theincreased hydrophobicity of these starting compounds will aid theirability to cross the blood-brain barrier (BBB) for target sites in theCNS.

As described above, the linkage between the halogenated phenol ring of astarting compound and the linked (drug) compound may include other typesof linkages apart from an ether linkage (for a hydroxyl or keto group onthe liberated compound) or a thioether linkage (for a sulfhydryl groupon the liberated compound). In addition, the breakable or cleavablelinkage between the halogenated phenol compound and the linked (drug)compound may also include a nitrogen linkage (see, e.g., FIG. 15),carbonyl linkage (see, e.g., FIG. 17) or a C—C bond (see, e.g., FIG.20). The following provides general formulas and examples for startingcompounds having these alternative linkages.

FIG. 15 provides a general class of compounds (Formula 15) according toembodiments of the present invention. According to these embodiments, acompound having an amino group (R₁—NH₂), such as a drug compound, may bebonded or linked by a nitrogen linkage to a halogenated phenol ring toform part of a starting compound of the present invention. The nitrogenof the nitrogen linkage (—NH—) links the rest of the compound (R₁) tothe halogenated phenol ring. X is a halogen in the ortho positionrelative to the hydroxyl group (—OH) on the phenol ring (i.e., X is ahalogen that is bonded to a carbon that is adjacent to a carbon bondedto the hydroxyl group (—OH) on the phenol ring). The halogen X may beselected from either iodine (I) or bromine (Br), but generally may notinclude fluorine (F) or chlorine (Cl). According to these embodiments,the nitrogen linkage (—Y—) may potentially be positioned anywhererelative to the halogen X and the hydroxyl group (—OH) on the phenolring. The identity of each of the other substituents, R₂, R₃, and R₄,present on the phenol ring may vary and may include, for example, ahydrogen, a hydroxyl, a sulfhydryl, an alkyl, a halogen, an amino, anitro, etc., groups. Unlike halogen X adjacent to the hydroxyl group ofthe phenol ring, substituents R₂, R₃, and R₄ may be any halogen atom.Furthermore, combinations of these other substituents, R₂, R₃, and R₄,present on the phenol ring may themselves form fused rings with thehalogenated phenol ring.

According to these embodiments in FIG. 15, when a compound of Formula 15comes in contact with an oxidizing agent or free radical or is presentin an oxidizing and/or free radical containing environment, the halogenX is cleaved and removed from the phenol ring and replaced with ahydroxyl group. This free radical attack or oxidation of the phenol ringfurther results in the breaking or cleavage of the nitrogen linkage(—NH—) between the drug compound and the phenol ring to release the drugcompound (R₁—NH₂) by bonding a hydrogen to form the amino group, and thenitrogen linkage on the phenol ring is replaced by a hydroxyl group. Inaddition to release of a halide (X⁻) and the drug compound, abenzenetriol-based compound (e.g., 1,2,4-benzenetriol or1,2,3-benzenetriol) may be formed. However, the exact formula name forthis product of the reaction will depend on the identity of additionalsubstituents, R₂, R₃, and R₄.

According to an embodiment of the present invention, FIG. 16 shows anexample of a starting compound (Compound 16) containing achemotherapeutic agent or drug, methotrexate, nitrogen linked to thehalogenated phenol ring, which may be used to treat cancer. According tothis example, when Compound 16 comes in contact with an oxidizing agentor free radical, or is present within an oxidizing and/or free radicalcontaining environment, the iodine (I) is cleaved and removed from thephenol ring and replaced with a hydroxyl group. This free radical attackor oxidation of the phenol ring further results in the breaking orcleavage of the nitrogen linkage to liberate or form the methotrexate inaddition to a benzenetriol compound (e.g., 1,2,4-benzenetriol) due to ahydroxyl group replacing the nitrogen linkage on the phenol ring, and ahalide. Thus, targeted delivery of the methotrexate chemotherapy may beachieved at a cancerous or tumor site in the body having high FROS.

FIG. 17 provides a general class of compounds (Formula 17) according toembodiments of the present invention. According to these embodiments, acompound having a carboxylic acid group (R₁—COOH), such as a drugcompound, may be bonded or linked by a carbonyl linkage to a halogenatedphenol ring to form part of a starting compound of the presentinvention. The carbon of the carbonyl linkage (—[C═O]—) links the restof the compound (R₁) to the halogenated phenol ring. X is a halogen inthe ortho position relative to the hydroxyl group (—OH) on the phenolring (i.e., X is a halogen that is bonded to a carbon that is adjacentto a carbon bonded to the hydroxyl group (—OH) on the phenol ring). Thehalogen X may be selected from either iodine (I) or bromine (Br), butgenerally may not include fluorine (F) or chlorine (Cl). According tothese embodiments, the carbonyl linkage (—[C═O]—) may potentially bepositioned anywhere relative to the halogen X and the hydroxyl group(—OH) on the phenol ring. The identity of each of the othersubstituents, R₂, R₃, and R₄, present on the phenol ring may vary andmay include, for example, a hydrogen, a hydroxyl, a sulfhydryl, analkyl, a halogen, an amino, a nitro, etc., groups. Unlike halogen Xadjacent to the hydroxyl group of the phenol ring, substituents R₂, R₃,and R₄ may be any halogen atom. Furthermore, combinations of these othersubstituents, R₂, R₃, and R₄, present on the phenol ring may themselvesform fused rings with the halogenated phenol ring.

According to these embodiments in FIG. 17, when a compound of Formula 17comes in contact with an oxidizing agent or free radical or is presentin an oxidizing and/or free radical containing environment, the halogenX is cleaved and removed from the phenol ring and replaced with ahydroxyl group. This free radical attack or oxidation of the phenol ringfurther results in the breaking or cleavage of the carbonyl linkage(—[C═O]—) between the (drug) compound and the phenol ring to release the(drug) compound (R₁—COOH) by bonding of a hydroxyl to the carbonylgroup, and the carbonyl linkage on the phenol ring is replaced by ahydroxyl group. In addition to release of a halide (X⁻) and the (drug)compound, a benzenetriol-based compound (e.g., 1,2,4-benzenetriol or1,2,3-benzenetriol) may be formed. However, the exact formula name forthis product of the reaction will depend on the identity of additionalsubstituents, R₂, R₃, and R₄.

According to an embodiment of the present invention, FIG. 18 shows anexample of a starting compound (Compound 18) containing an antibiotic,penicillin or its derivatives, carbonyl linked to the halogenated phenolring, which may be used to treat infection. The R group may varyaccording to the type or derivative of penicillin used. For example,“penicillin” may include penicillin G, penicillin V, ampicillin,amoxicillin, etc. For penicillin G, the R group is a benzyl, whereas theR group is a phenoxymethyl for penicillin V. According to this example,when Compound 18 comes in contact with an oxidizing agent or freeradical, or is present within an oxidizing and/or free radicalcontaining environment, the iodine (I) is cleaved and removed from thephenol ring and replaced with a hydroxyl group. This free radical attackor oxidation of the phenol ring further results in the breaking orcleavage of the carbonyl linkage to liberate or form the penicillinmolecule in addition to a benzenetriol compound (e.g.,1,2,4-benzenetriol) due to a hydroxyl group replacing the nitrogenlinkage on the phenol ring, and a halide. Thus, targeted delivery of thepenicillin may be achieved to sites of infection in the body having highFROS.

FIG. 19 provides some additional examples of starting compoundscontaining drugs carbonyl linked to a halogenated phenol ring. FIG. 19Ashows an example of a starting compound with aspirin carbonyl linked toa halogenated phenol ring. Upon cleavage in the presence of FROS,aspirin is formed along with a benzenetriol compound and a halide. FIG.19B shows an example of a starting compound with naproxen carbonyllinked to a halogenated phenol ring. Upon cleavage in the presence ofFROS, naproxen is formed along with a benzenetriol compound and ahalide. Finally, FIG. 19C shows an example of a starting compound withibuprofen carbonyl linked to a halogenated phenol ring. Upon cleavage inthe presence of FROS, ibuprofen is formed along with a benzenetriolcompound and a halide. Each of these example compounds of the presentinvention may be taken or administered to achieve targeted delivery ofthe drug to sites of inflammation and/or pain for relief of thesesymptoms.

FIG. 20 provides a general class of compounds (Formula 20) according toembodiments of the present invention. According to these embodiments, acompound having an alcohol group (R₁—CH₂—OH), such as a drug compound,may be bonded or linked by a C—C bond to a halogenated phenol ring toform part of a starting compound of the present invention. The C—C bondlinks the rest of the compound (R₁) to the halogenated phenol ring. X isa halogen in the ortho position relative to the hydroxyl group (—OH) onthe phenol ring (i.e., X is a halogen that is bonded to a carbon that isadjacent to a carbon bonded to the hydroxyl group (—OH) on the phenolring). The halogen X may be selected from either iodine (I) or bromine(Br), but generally may not include fluorine (F) or chlorine (Cl).According to these embodiments, the C—C bond may potentially bepositioned anywhere relative to the halogen X and the hydroxyl group(—OH) on the phenol ring. The identity of each of the othersubstituents, R₂, R₃, and R₄, present on the phenol ring may vary andmay include, for example, a hydrogen, a hydroxyl, a sulfhydryl, analkyl, a halogen, an amino, a nitro, etc., groups. Unlike halogen Xadjacent to the hydroxyl group of the phenol ring, substituents R₂, R₃,and R₄ may be any halogen atom. Furthermore, combinations of these othersubstituents, R₂, R₃, and R₄, present on the phenol ring may themselvesform fused rings with the halogenated phenol ring.

As noted above and further below, a C—C bond or linkage between ahalogenated phenol ring and the rest of the compound (R₁) in somecircumstances may not generally be cleaved during or following thedehalogenation reaction. Indeed, the starting compound (MIT) in FIG. 27below is found to generally not be cleaved with the dehalogenationreaction. However, other starting compounds may be cleaved to form thealcohol in conjunction with the reaction. The full set of reasons forwhy cleavage does result in some circumstances (i.e., for some startingcompounds), but not for others, are not entirely clear. However, it isbelieved that as a general rule R₁ groups (according to FIG. 20)comprising an aromatic ring near the C—C bond or linkage may generallybe cleaved during or following a dehalogenation reaction, whereas thoseR₁ groups lacking an aromatic ring near the C—C bond may resistcleavage, which may reflect the different electronic states near thebond. Given the (surprising) discovery described herein that cleavagegenerally occurs with the various types of bonds or linkages, it isfurther surprising that cleavage would not then generally occur forcompounds linked by the C—C bond given the bond energies. Further workwould be needed to elucidate the mechanisms underlying the cleavagereaction and why some compounds may undergo cleavage while others donot.

According to these embodiments in FIG. 20, when a compound of Formula 20comes in contact with an oxidizing agent or free radical or is presentin an oxidizing and/or free radical containing environment, the halogenX is cleaved and removed from the phenol ring and replaced with ahydroxyl group. Depending on the compound, this free radical attack oroxidation of the phenol ring may potentially further result in thebreaking or cleavage of the C—C bond between the (drug) compound and thephenol ring to release the (drug) compound (R₁—CH₂—OH) by bonding of ahydroxyl to the carbon, and the C—C bond on the phenol ring is replacedby a hydroxyl group. In addition to release of a halide (X⁻) and the(drug) compound, a benzenetriol-based compound (e.g., 1,2,4-benzenetriolor 1,2,3-benzenetriol) may be formed. However, the exact formula namefor this product of the reaction will depend on the identity ofadditional substituents, R₂, R₃, and R₄.

According to other embodiments, an organometallic starting compound ofthe present invention may comprise a halogenated phenol ring directlybonded to a metal or metalloid atom or element, which may be part of anR-group (i.e., via a “metal linkage”). For example, the metal atom orelement may be a toxic element, such as mercury (Hg), which is bound tothe halogenated phenol ring by the metal linkage, and the metal atom orelement may be part of a larger R-group. When such a compound comes incontact with a FROS-containing environment, the metal linkage may becomecleaved as a result of the dehalogenation reaction to relieve the toxicmetal, such as mercury, at the site. In the case of mercury, the Hg atombonded to the halogenated phenol ring may retain a charge and thus beformulated as a salt with a counter anion, such as chloride. Such acomposition may be used to deliver and release the cytotoxic metal to asite of a cancerous tissue or tumor.

As described above in connection with FIGS. 6 and 7, polymers of two ormore halogenated phenol rings (with or without empty or “spacer” units)may be utilized for delivering multiple drugs of the same or differenttype to sites of high FROS in the body, which may be associated withinflammation or disease. By way of example, these figures and theirassociated text focus on the use of an ether linkage between each of theunits. However, as described above and in connection with immediatelypreceding FIGS. 15-20, such polymers of two or more halogenated phenolrings in FIGS. 6 and 7 may instead be linked by one of the alternativetypes of linkages including thioether linkages, nitrogen linkages,carbonyl linkages, sulfinyl linkages or possibly C—C bonds. To visualizethese structures, the ether linkages in formulas in FIGS. 6 and 7 maysimply be replaced with the respective alternative linkage. Although thestructure and other substituents may otherwise be the same, some of theproducts of the reaction may be slightly different due to a differentsubstituent being produced by the alternative linkage. For example,instead of the remaining chain having a hydroxyl group in place of thecleaved ether linkage, an amino group may be left in place of thecleaved nitrogen linkage, or a carboxyl group may be left in place ofthe cleaved carbonyl linkage, etc. It also envisioned that combinationsof different types of linkages could be used between differentneighboring units of a chain or polymer.

One of the main challenges in treating central nervous system (CNS)diseases is taking or administering pharmaceutical drug compounds thatare able to cross the formidable blood-brain barrier (BBB) to exerttheir therapeutic effect in cells and tissues of the CNS. Largemacromolecules and hydrophilic small molecules generally have difficultycrossing the BBB and thus insufficient availability in the brain withoutactive transport. However, hydrophobic or lipophilic small molecules maybe able to diffuse more readily across the membranes of the BBB andenter the brain. One key advantage of embodiments of the presentinvention is that the presence of a halogen(s), especially iodine (I),on the phenol ring of compounds of the present invention increases theirhydrophobicity and improves the ability of these compounds to diffuseacross the BBB and exert their effects in the brain. This is especiallyimportant for drugs intended for use in treating CNS diseases.

Improving the ability of CNS drugs to cross the BBB may have enormousbenefits in treating CNS disease. For example, L-DOPA is the goldstandard for treating Parkinson's disease, but the L-DOPA compound isslow to cross the BBB and causes unwanted side effects in peripheraltissues outside of the brain. According to an embodiment of the presentinvention, for example, a 3-hydroxy-3′-iodo-thyronamine compound(Compound 8) shown in FIG. 8A (or a 3-hydroxy-3′-iodo-thyronine compoundin FIG. 8B) may diffuse across the BBB more easily largely due to thepresence of the iodine on the phenol ring. Once Compound 8 crosses theBBB, it may exert its effects in a targeted region of the brain as aresult of being converted to dopamine by the dehalogenation and cleavagereaction in the presence of free radicals and/or oxidative agents (i.e.,FROS) present in affected brain tissue of individuals suffering fromParkinson's disease. Similarly, the 3-hydroxy-3′-iodo-thyronine compoundin FIG. 8B may also cross the BBB and form L-DOPA in the presence ofFROS, which may then be converted into dopamine. According to anotherembodiment described below in connection with FIG. 27 for example, amonoiodotyrosine (MIT) compound may diffuse more easily across the BBBand become converted by a dehalogenation reaction without cleavage toyield L-DOPA in the brain, which may then be converted into dopamine(other non-cleavage examples are also provided below for the productionof dopamine or L-DOPA in targeted regions of the brain). Therefore,compounds of the present invention intended to treat CNS diseases may betaken or administered at lower doses since a greater proportion of thesecompounds in the bloodstream will cross the BBB and exert targetedeffects in the brain.

Another key advantage of embodiments of the present invention is that bylinking a drug compound to a halogenated phenol ring, the normalbiological activity or effect of the drug compound may be masked (i.e.,sterically blocked or hindered) until its release at the target site ofinflammation or disease. For example, the halogenated phenol linkeddrug(s) may not be able to bind to, interact with, modify, etc., theirmolecular or cellular targets in cells or tissues until the drugcompound is liberated as described herein. The presence of a halogenatedphenol ring linked to the drug compound may also sterically hinder theability of drug metabolizing enzymes to bind and modify the drugcompound until its release at the target site. The covalently attachedhalogenated phenol ring may further serve to help shield or protect thedrug from other non-specific chemical or enzymatic degradation until itsrelease at the target site, thus potentially reducing side effects,and/or provide a more sustained release of the drug. In addition,shielding of the drug by the halogenated phenol ring may also help toblock unintended or abusive use of the drug by other routes ofadministration (e.g., inhalation). It may also be true that by achievingtargeted delivery, lower dosages may be required for a given therapeuticeffect.

Thus, the halogenated phenol ring provides a “pro-drug” format for theprotection and masking of the conjugated drug compound until its releaseat the target site. Upon removal of the blocking phenol ring, thecompound or drug may be freed to bind a target or receptor or to exertits activity. For example, L-DOPA is used to effectively treatParkinson's disease. However, L-DOPA causes many unwanted side effectsas a result of its conversion to dopamine by DOPA decarboxylase inperipheral tissues outside of the brain. Currently, L-DOPA isadministered in combination with another drug (e.g., Carbidopa) whichdoes not cross the BBB to suppress these undesired effects by blockingthe conversion of L-DOPA to dopamine in these other tissues. One keyadvantage of dopamine or L-DOPA releasing or producing compounds of thepresent invention, such as the halogenated phenol compound linked todopamine or L-DOPA, such as in FIG. 8, reverse T3 in FIG. 22,monoiodo-phenylalanine or the monoiodo-tyrosine compound in FIG. 27, areeach not recognized by the DOPA-decarboxylase enzyme. Accordingly, thedopamine or L-DOPA releasing or producing compounds of the presentinvention may be taken or administered alone (i.e., without or with onlyminimal or small doses of Carbidopa) because their conversion tobioactive dopamine might be limited to desired sites of inflammation anddisease in the CNS, which may be deficient in levels of dopamine.

In addition to providing the targeted delivery of a drug compound,compounds of the present invention have the further advantage ofproviding an anti-oxidant and/or free radical scavenging benefit.Following administration or taking of a halogenated phenol compoundaccording to embodiments of the present invention to an individual, thestarting compound undergoes dehalogenation and cleavage of the relevantlinkage in the presence of free radicals or oxidative agents. Duringthis dehalogenation and cleavage reaction, which may result in therelease of a drug compound, free radicals or oxidative agents thattrigger the reaction are consumed. Thus, the amounts of FROS at the sitemay be reduced or depleted by the reaction. In addition, one of theproducts of the dehalogenation and cleavage reaction is likely to be abenzenetriol- or bezenetetrol-based compound, which also has stronganti-oxidant and/or free radical scavenging properties to consume morefree radicals or oxidative agents in subsequent or additional reactionstep(s). Generally speaking, increasing the number of hydroxyl groups onthe benzene-containing product of the reaction may also make thecompound more reductive and thus a more potent anti-oxidant and/or freeradical scavenger.

According to some embodiments, if the compound of the present inventioncomprises two or more halogenated phenol rings linked together by anether linkage(s) or group(s), then the anti-oxidant and/or free radicalscavenging benefit may be multiplied further by consuming an evengreater number of free radicals or oxidative agents in multipledehalogenation reaction(s). Therefore, one of the key benefits andadvantages of compounds of the present invention, in addition totargeted delivery of a drug compound, is that free radicals and/oroxidative agents may be consumed at or during multiple reaction steps(i.e., during the dehalogenation reaction and by virtue of the one ormore anti-oxidant and/or free radical scavenging products of thereaction).

The combination of targeted drug delivery to sites of disease and/orinflammation, increased stability, sustained release, antioxidant and/orfree radical scavenging properties and/or masked bioactivity innon-targeted tissues with halogenated phenol compounds of the presentinvention may provide enormous benefit and efficacy for improvedtreatment of disease over existing therapies. In addition, compounds ofthe present invention intended for the treatment of CNS diseases mayhave the further benefit of having increased hydrophobicity due to thepresence of halogens and phenol ring(s), which may greatly improve theability of these drug compounds to cross the blood-brain barrier.

According to another broad aspect of the invention, a compound accordingto some embodiments may provide anti-oxidant and/or free radicalscavenging benefits without the targeted delivery of a drug compound perse (i.e., without the targeted delivery and release of a drug compoundthat is linked to the halogenated phenol ring), although any antioxidantand/or free radical scavenging compound products of the reaction maythemselves be thought of as a “drug compound.” In other words, thedehalogenation and cleavage reaction may be used primarily to consumethe oxidizing agents and/or free radicals (i.e., FROS). In addition, asmentioned above, products of this reaction, such as quinones, etc., maythemselves further function as free radical and/or oxidative scavengers.Although the compounds according to these embodiments are used primarilyas anti-oxidant, anti-inflammatory and/or FROS scavenging agents, itcannot be ruled out that some products of the dehalogenation andcleavage reaction from these compounds may have other bioactivities(i.e., not related to anti-oxidant, anti-inflammatory and/or FROSscavenging functions). However, it may be preferred that according tothese embodiments, any other (non-related) bioactivities of suchproducts be minimal or non-existent.

Compounds according to these embodiments having anti-oxidant and/or freeradical scavenging effects (i.e., FROS scavengers) may be taken by, oradministered, provided or given to, an individual to avoid cellular ortissue damage or aging caused by oxidizing agents and/or free radicalsor to lessen the pathological consequences and/or symptoms of disease,inflammation or normal aging which are mediated by oxidizing agentsand/or free radicals. These anti-oxidant and/or free radical scavengingeffects may be site-specific or systemic depending on the route ofadministration and/or the nature of the condition being treated. Forexample, such compounds having anti-oxidant and/or free radicalscavenging effects may be used to treat particular inflammation-mediateddiseases, such as autoimmune disease, arthritis, atherosclerosis,ischemic bowel disease, multiple sclerosis (MS), retrolental fibroplasia(RLF), and cardiovascular disease, as well as secondary freeradical-mediated conditions associated with various diseases, such ascachexia or sepsis, and to protect the skin from damage that mightotherwise result from solar or radiation exposure. In addition,compounds of the present invention may be used to offset FROS exposureand tissue damage during ischemic and/or reperfusion conditions, such asischemia and/or reperfusion associated with myocardial infarction.

FIG. 21 provides a general class of compounds (Formula 21) according toembodiments of the present invention which may be used as ananti-oxidant, free radical scavenger, and/or anti-inflammatory agent.According to these embodiments, a substituent (R₁) may be bonded by anether or thioether linkage to a halogenated phenol ring to form part ofthe compound of the present invention. The ether or thioether linkage(—Y—) may be (i) an ether linkage if Y is an oxygen atom and the —YHgroup on the R₁—YH product of the cleavage reaction is a hydroxyl groupor (ii) a thioether linkage if Y is a sulfur atom and the —YH group onthe R₁—YH product of the cleavage reaction is a sulfhydryl group. X is ahalogen in the ortho position relative to a hydroxyl group (—OH) on thephenol ring (i.e., X is a halogen that is bonded to a carbon that isadjacent to a carbon bonded to a hydroxyl group (—OH) on the phenolring). The halogen X may be selected from either iodine (I) or bromine(Br), but generally may not include fluorine (F) or chlorine (Cl). Thedifference between embodiments shown in FIG. 21 and those shown in FIGS.1-20 above is that the compound R₁—YH released by the reaction in FIG.21 is not necessarily a drug compound per se and may include a broadergroup of compounds and chemical groups, some of which may function asFROS scavengers as well. According to these embodiments, R₁ may include,for example, a hydrogen, an alkyl, an aryl, an amino, a nitro, etc.,groups. According to some of these embodiments, a varied class ofhalogenated diphenyl or dihydroxy-diphenyl compounds are proposed (seeFIG. 23 below).

According to these embodiments in FIG. 21, the ether or thioetherlinkage (—Y—) may be positioned anywhere on the phenol ring not occupiedby the ortho-positioned hydroxyl group and halogen X (i.e., on any ofthe remaining carbons of the phenol ring). Similarly, additionalsubstituents R₂, R₃, and R₄ may be positioned anywhere on the phenolring not occupied by the ortho-positioned hydroxyl group and halogen X(i.e., on any of the remaining carbons of the phenol ring). The identityof each of the other substituents, R₂, R₃, and R₄, present on the phenolring may vary and may include, for example, a hydrogen, a hydroxyl, asulfhydryl, an alkyl, a halogen, an amino, a nitro, etc., groups. Unlikehalogen X adjacent to the hydroxyl group of the phenol ring,substituents R₂, R₃, and R₄ may be any halogen atom. According to somealternative embodiments, one, two or three of these variablesubstituents may be hydrogen. Furthermore, combinations of these othersubstituents, R₂, R₃, and R₄, present on the phenol ring may themselvesform fused rings with the halogenated phenol ring.

According to some embodiments, the addition of a second halogen ortho tothe hydroxyl group may influence the acidity of the hydroxyl groups dueto the electron withdrawing character of the halogen. Thus, atphysiological pH, the O⁻ form may predominate over the —OH form of thesubstituent. This ionization of the substituent may prove useful in somecircumstances for improved solubility and/or diffusion through cellularmembranes and tissues.

According to embodiments of the present invention, when a compound ofFormula 21 comes in contact with an oxidizing agent or free radical, oris present in an oxidizing and/or free radical containing environment,the halogen X is cleaved and removed from the phenol ring and replacedwith a hydroxyl group. This free radical attack or oxidation of thephenol ring further results in the breaking or cleavage of the ether orthioether linkage (—Y—) to release a compound R₁—YH, and the ether orthioether linkage is replaced by a hydroxyl group on the phenol ring. Inaddition to release of a proton (H⁺; not shown), a halide (X⁻) andcompound R₁—YH, a benzenetriol-based or hydroxyhydroquinone-basedcompound (e.g., 1,2,4-benzenetriol) may be formed. However, the exactformula name for this product of the reaction will depend on theidentity of the additional substituents, R₂, R₃, and R₄. In addition toan oxidizing agent or free radical being consumed in the dehalogenationand cleavage reaction, the benzenetriol-based product of the reactionmay also function as an anti-oxidant and/or free radical scavenger in asubsequent reaction. Depending on the exact identity of the R₁substituent, the product compound R₁—YH may also function as ananti-oxidant and/or free radical scavenger.

Alternatively, the type of linkage used for these FROS scavengingembodiments may vary and may instead include a nitrogen linkage, acarbonyl linkage, a sulfinyl linkage, or a C—C bond in place of theether or thioether (Y) linkage. Such embodiments would functionsimilarly in consuming FROS during a dehalogenation and cleavagereaction but would produce slightly different products with a differentsubstituent at the site of the alternative linkage. The structures ofthese alternative embodiments may be deduced from the descriptionherein, particularly in reference to FIGS. 15, 17 and 20.

As shown in FIG. 22, reverse T3 or rT3 (i.e., 3,3′,5′-triiodothyronine)could be used as an anti-oxidant, free radical scavenger, and/oranti-inflammatory agent. As shown in FIG. 22, when the reverse T3compound comes in contact with an oxidizing agent or free radical, or ispresent in an oxidizing and/or free radical containing environment, theiodine (I) on the outer phenol ring of reverse T3 is cleaved andreplaced with a hydroxyl group. This free radical attack or oxidation ofthe outer phenol ring of reverse T3 further results in the breaking orcleavage of the ether linkage to form an iodo-benzenetriol compound, amonoiodo-tyrosine compound (MIT), and a halide. In addition to anoxidizing agent or free radical being consumed in the dehalogenation andcleavage reaction, the iodo-benzenetriol and monoiodo-tyrosine productsof the reaction may also function as an anti-oxidant and/or free radicalscavenger in a subsequent reaction. However, the use of reverse T3strictly as an anti-oxidant or free radical scavenger may be problematicdue to the potential biological activity of a downstream product of thereaction (i.e., L-DOPA and/or dopamine from MIT—see discussion below inreference to FIG. 27).

According to other embodiments, an antioxidant compound of the presentinvention may comprise a halogenated phenol ring directly bonded to ametal or metalloid atom or element, which may be part of an R-group(i.e., via a “metal linkage”). For example, such a composition maycomprise boron (B) bonded three ways to three R-groups, R, R′, R″, oneor more of which may be a halogenated phenol ring. When such a compoundcomes in contact with a FROS-containing environment, the metal linkagebetween the boron atom and the one or more halogenated phenol rings maybecome cleaved as a result of the dehalogenation reaction to consumeFROS. In addition to the benzentriol-based compounds formed, a boricacid or sodium borate molecule may also be generated by the reaction.

FIGS. 23A-D provide general classes of diphenyl compounds comprising ahalogenated phenol ring linked to another benzene ring. X is a halogenand may be either iodine or bromine (but may preferably be iodine). Theother substituents, R₂, R₃, R₄, R₅, R₆, R₇, R₈, and R₉, may vary and mayinclude, for example, a hydrogen, a hydroxyl, a sulfhydryl, an alkyl, ahalogen, an amino, a nitro, etc., groups. According to some alternativeembodiments, one, two, three, four, five, six, seven or eight of thesevariable substituents may be hydrogen. FIG. 23A represents a generalclass of diphenyl ether or thioether compounds. Similarly to FIG. 21,the ether or thioether linkage (—Y—) in FIG. 23A may be an ether linkageif Y is an oxygen atom or a thioether linkage if Y is a sulfur atom. Thecleavage reaction would form products similarly as shown in FIG. 21.

As described above, the ether (or thioether) linkage of the startingcompound formula in FIG. 23A may alternatively be replaced with, forexample, a nitrogen linkage (FIG. 23B; a diphenylamine structure), acarbonyl linkage (FIG. 23C; i.e., a benzophenone), a sulfinyl linkage,or a C—C bond (FIG. 23D). Although the products of a cleavage reactioninvolving one of these alternative starting compounds may be differentdue to the different substituent formed at the site of the alternativelinkage, these alternative starting compounds may be used similarly toconsume FROS. As a few examples, these compounds may include3-iodo-4,4′-dihydroxy-benzophenone (forming a 4-carboxy-phenol in FROS),3-iodo-4-hydroxy-phenylsulfoxide (forming p-toluene sulfonic acid),3-iodo-4-hydroxy-diphenyl amine (forming benzyl amine), ordiiodo-hydroxy-diphenylmethane (forming benzyl alcohol).

FIGS. 23E-H provide more limited classes of dihydroxy-diphenyl compoundsaccording to embodiments of the present invention which may be used asan anti-oxidant, free radical scavenger, and/or anti-inflammatory agent.These formulas correspond to those in FIGS. 23A-D, respectively, withone of the substituents on the ring being a hydroxyl group and at leasttwo of the other substituents being a hydrogen. The substituents on theα-ring would include at least two hydrogens. For example, FIG. 23E(corresponding to FIG. 23A) provides a subset of compounds falling underthe more general formulas of FIG. 21 wherein R₁ is an aryl group, andwhich may include a variety of dihydroxy-diphenyl ether compounds(DHDPEs). According to these embodiments, in contrast to FIGS. 23A-D,each of the variable substituents R₂, R₃, and R₄ may be either ahydrogen or a halogen. X is a halogen and may be either iodine orbromine (but may preferably be iodine). Likewise, if one or moresubstituents R₂, R₃, and R₄ are a halogen, they may be either iodine orbromine (but may preferably be iodine). Similarly to FIG. 21, the etheror thioether linkage (—Y—) in FIG. 23E may be an ether linkage if Y isan oxygen atom or a thioether linkage if Y is a sulfur atom. Thecleavage reaction would form products similarly as shown in FIG. 21.

FIG. 24 shows a specific example embodiment of the present inventionaccording to FIG. 23E of a 3-iodo-4,4′-dihydroxy-diphenyl ether compoundthat may be used as an anti-oxidant, free radical scavenger, and/oranti-inflammatory agent. Such a compound may be used to treatinflammation or diseases associated with inflammation, such asarthritis, etc., or to reduce free radical or oxidative load generallywithin the body. According to this example, when the3-iodo-4,4′-dihydroxy-diphenyl ether compound comes in contact with anoxidizing agent or free radical, or is present in an oxidizing and/orfree radical containing environment, the iodine (I) is cleaved andremoved from the phenol ring and replaced with a hydroxyl group. Thisfree radical attack or oxidation of the phenol ring further results inthe breaking or cleavage of the ether linkage to form or produce abenzenetriol (or hydroxyhydroquinone) compound, a hydroquinone, and ahalide. In addition to an oxidizing agent or free radical being consumedin the dehalogenation and cleavage reaction, both of the benzenetriol(or hydroxyhydroquinone) and hydroquinone products of the reaction mayfurther function as an anti-oxidant and/or free radical scavenger in asubsequent reaction. According to a similar embodiment, a3,3′-diiodo-4,4′-dihydroxy-diphenyl ether compound is proposed havingtwo halogens on one of the phenol rings.

As described above, the ether (or thioether) linkage of the startingcompound formula in FIG. 23E may alternatively be replaced with anitrogen linkage (FIG. 23F; a diphenylamine structure), a carbonyllinkage (FIG. 23G; i.e., a benzophenone), or a C—C bond (FIG. 23H).Although the products of a cleavage reaction involving one of thesealternative starting compounds may be different due to the differentsubstituent formed at the site of the alternative linkage, the reactionmay be used similarly to consume FROS.

According to some of these embodiments, a pharmaceutical composition isprovided comprising any compound(s) having a structural formulaaccording to FIGS. 23A-H in combination with a pharmaceuticallyacceptable carrier.

According to other embodiments, one or more of these halogenateddiphenyl or dihydroxy-diphenyl (DHDP) compounds shown in FIG. 23 areproposed for use as a sunscreen topically applied to the skin. Suchdihydroxy-diphenyl compounds may include those having any of thealternative linkages shown between the two phenyl groups. For example,one or more halogenated dihydroxy-diphenyl ether (DHDPE) compoundsaccording to FIG. 20A are proposed for use in a sunscreen composition.In addition, dihydroxy-diphenyl (DHDP) compound(s) similar to those inFIG. 23 but lacking the halogen substituent (X) (i.e., any of theformulas in FIG. 23 with a hydrogen replacing X and substituents R₂, R₃,and R₄ each being a hydrogen) are also proposed for this purpose. Thephenol rings of these compounds are believed to be effective in directlyabsorbing UV light with some amount of a sun protection factor (SPF).Furthermore, according to the reactions described herein, halogenateddiphenyl or dihydroxy-diphenyl compounds of FIG. 23 having one or morehalogens (e.g., iodines) on the phenol rings may also be effective atscavenging FROS produced by sunlight exposure in the skin (e.g., in theextracellular spaces) via the dehalogenation and cleavage reaction,perhaps in addition to functioning as a direct sunlight absorber.Therefore, a variable number of halogens (i.e., between 0-4 halogens oriodines) may be placed on the phenol rings of these compounds assubstituents.

Radiation from the sun can cause the formation of damaging oxidantsand/or free radicals by interaction with molecules in the skin.Therefore, by topically applying any of the halogenated diphenyl or DHDPcompound(s) of FIG. 23 (including any halogenated DHDPE compounds) tothe skin, the FROS produced by the solar radiation may be consumed bythe dehalogenation reaction prior to the cells and tissue of the skinbecoming damaged thereby (possibly in addition to protecting the skin bydirect absorption of UV light). Moreover, increasing the number ofhalogens (e.g., iodines) on the phenol rings is believed to furtherincrease the amount of direct absorption or blocking of UV light by thephenol ring(s). In addition, these halogenated compounds (especiallythose with one or more iodines) can be “dissolved” into hydrophobic oilsor lotions of a topically applied sunscreen composition due to their ownhydrophobicity. As stated above, however, if there are no iodines orother halogens on the rings, then the compound will not function as FROSscavenger via the dehalogenation/cleavage reaction, but may still beeffective as a direct UV absorber.

According to these embodiments, one or more such halogenated ornon-halogenated (e.g., iodinated or non-iodinated) diphenyl ordihydroxy-diphenyl compound(s) of FIG. 23 may be combined with anysuitable sunscreen vehicle(s), excipient(s) and/or carrier(s) fortopical application to the skin (e.g., as a lotion, oil, salve, etc.) asdescribed herein or known in the art. These sunscreen compositions maybe spread, rubbed, or sprayed onto the skin. Any suitable ingredient(s)or vehicle(s), such as oils including olive oil, coconut oil, mineraloil, etc., emollients, shea butter, emulsifiers, etc., that are normallyused as part of, or in formulating, tanning or sunscreen lotions, etc.,may be used as part of the present sunscreen compositions in combinationwith any of these halogenated or non-halogenated compound(s) for topicalapplication. Indeed, some of these additional ingredients, such as oils,may aid in wicking, pulling or absorbing the compounds deeper into theskin. The sunscreen composition may be a water-in-oil emulsion and mayinclude an aqueous phase and an oil phase with or without an emulsifier.Sunscreen compositions that are spray applied to the skin may include apropellant as an additional vehicle or ingredient. As an examplesunscreen formulation, any of the halogenated DHDPE compounds describedherein may be formulated as a 0.1% suspension in coconut oil to providea topical lotion, which may be applied topically to provide additionalepidermal hydration and protect the skin from harmful solar UVradiation. For a description of suitable sunscreen vehicles oringredients that may be used in combination with the proposedhalogenated (and/or non-halogenated) dihydroxy-diphenyl compound(s) aspart of a sunscreen composition of the present invention, see, e.g.,U.S. Pat. Nos. 5,188,831; 5,250,289; 5,935,556; and 6,858,200, theentire contents and disclosures of which are incorporated herein byreference Embodiments of the present invention further include methodsof topically applying, spreading, spraying, etc., a sunscreencomposition of the present invention to the skin of an individual toprovide sun protection.

According to some of these embodiments, DHDPE compounds that may be usedin a sunscreen composition may include those having hydroxyl groups atthe 4 and 4′ positions. Examples of these 4,4′-hydroxy compoundembodiments include those having iodines at one or more of the 3-, 5-,3′- or 5′-position(s) of the DHDPE molecule (in any possiblecombination), such as 3-iodo-DHDPE, 3,5-diiodo-DHDPE, 3,3′-diiodo-DHDPE,3,5,5′-triiodo-DHDPE, 3,3′,5,5′-tetraiodo-DHDPE, etc. For example, the3-iodo-DHDPE is shown in FIG. 24.

As supported by the classes of compounds and examples in FIGS. 21-24,embodiments of the present invention may potentially includeanti-oxidant, anti-inflammatory and/or FROS scavenging polymers ofhalogenated phenol ring units of any length (i.e., halogenated oriodinated polyphenols) with each unit of the polymer linked by an etheror thioether linkage to its neighboring unit(s) of the polymer. As shownin FIG. 25, individual phenol ring units may be dehalogenated andreleased sequentially (one at a time) along with a benzenetriol or likeproduct (depending on chemical formula) and a halide through discretedepolymerization reaction events or steps triggered by exposure of thepolymer to oxidizing agents and/or free radicals. The number of units ina polymer may vary widely and may include polymers of 2-200 units inlength, or alternatively polymers of 2-100 units, 2-50 units, 2-25units, 2-10 units, or 2-5 units in length, but longer polymers are alsopossible. According to some embodiments, the polymers may have a minimumof three (3) units in a range having the same upper limits. In referenceto FIG. 25, the number of units will depend on the number of units (n)inserted between the first and last unit in the chain or polymer. Ifn=0, then the total number of units in the chain or polymer would be two(2), and the starting molecule would be able of undergoing only onedehalogenation and cleavage reaction. If n=1, then the total number ofunits in the chain or polymer would be three (3), and the startingmolecule would be able to undergo two rounds of dehalogenation andcleavage reactions, and so on. Therefore, the number (n) may vary fromzero (0) to about the number of total units in the chain desired (e.g.,10, 25, 50, 100, 200, etc.).

Each round of dehalogenation and ether cleavage will consume anoxidizing agent or free radical from the chemical environment of thehalogenated phenol ring polymer. In addition to consuming an oxidizingagent or free radical during the dehalogenation and cleavage reactionitself, the benzenetriol or like products of the cleavage anddepolymerization reaction may further function as an anti-oxidant and/orfree radical scavenger in a subsequent or side reaction. Thus, compoundsor polymers according to embodiments shown in FIG. 25 may be used as aFROS scavenger with extended activity.

The substituents on each unit of the polymer or chain shown generally inFIG. 25 may vary similarly as described above in reference to othercompounds. The substituents (R₁, R₂, R₃, and R₄), present on the phenolring may vary and may each be, for example, a hydrogen, a hydroxyl, asulfhydryl, an alkyl, a halogen, an amino, a nitro, etc., group. Theleading or first unit in the chain will have four potentially variablesubstituents (R₁, R₂, R₃, and R₄), whereas the remaining units in thechain will have only three potentially variable substituents (R₁, R₂ andR₃) due to their being one less unoccupied carbon available on the ringsof the remaining units. Although R₁, R₂ and R₃ may be the same on eachunit and/or occupy the same positions, the identity of R₁, R₂ and R₃ mayinstead be different between units of the chain and/or occupy differentpositions on each respective unit of the chain.

According to another broad aspect of the present invention, a compoundaccording to some embodiments may undergo dehalogenation withoutcleavage. According to these embodiments, a compound containing ahalogenated phenol ring may contain a different type of bond (e.g., aC—C, C—N, or C—H bond), which is not generally cleaved when the phenolis dehalogenated in the presence of free radicals and/or oxidativeagents. As observed, destabilization of the electron cloud of the phenolring as a result of dehalogenation, does not appear to result in thecleavage of the C—C, C—N, or C—H bond in these cases. Instead, only thehalogen of the phenol ring is replaced with a hydroxyl group to reach alower energy state. As a caveat, a C—C bond or linkage may becomecleaved in some circumstances depending on the identity of the startingcompound and the type of substituent linkage by the C—C bond. In othercircumstances, however, a compound according to embodiments of thepresent invention may be designed to exploit this outcome with a C—C,C—N, or C—H bond (i.e., without a cleavable linkage), such that thecompound will undergo a different kind of conversion or modification inresponse to free radicals and/or oxidative agents without cleavage ofthe C—C, C—N, or C—H bond. As an advantage, this approach may bepreferred to avoid other cleavage products of the reaction.

FIG. 26 provides a general class of compounds (Formula 26) which may beused according to embodiments of the present invention when it isdesired that the product of the dehalogenation reaction be the same asthe original or starting compound of Formula 26 except for thereplacement of a halogen X on the phenol ring with a hydroxyl group.According to these embodiments, a halogenated phenol ring is bonded tofour additional substituents R₁, R₂, R₃, and R₄. X is a halogen in theortho position relative to a hydroxyl group (—OH) on the phenol ring(i.e., X is a halogen that is bonded to a carbon that is adjacent to acarbon bonded to a hydroxyl group (—OH) on the phenol ring). The halogenX may be selected from either iodine (I) or bromine (Br), but generallymay not include fluorine (F) or chlorine (Cl). The identity of each ofthe remaining substituents R₁, R₂, R₃, and R₄ may vary and may include,for example, a hydrogen, a hydroxyl, a sulfhydryl, an alkyl, a halogen,an amino, a nitro, etc., groups. However, in contrast to the embodimentsdescribed above, these compounds do not have an ether or thioether bondor linkage on the phenol ring that could be cleaved as a result of thedehalogenation reaction. As a result, the product of the reactionclosely resembles the starting compound except for the replacement ofthe halogen at the ortho-position relative to the hydroxyl group on thephenol ring with a hydroxyl group. According to some embodiments,substituents R₁, R₂, R₃, and R₄ would not include an aromatic ring,which is believed to encourage cleavage with dehalogenation.

According to these embodiments in FIG. 26, when a compound of Formula 26comes in contact with an oxidizing agent or free radical, the halogen Xis cleaved and removed from the phenol ring and replaced with a hydroxylgroup. However, unlike compounds containing a cleavable linkage on thephenol ring, the C—C bond in this case is not cleaved in conjunctionwith, or spontaneously as a result of, the cleavage and removal of thehalogen as part of the reaction. Therefore, in addition to a halide(X⁻), the product of the reaction is an ortho-hydroxy phenyl compoundwith the substituents R₁, R₂, R₃, and R₄ still bonded to the phenolring. Compounds or drugs formed by the dehalogenation reaction proposedin FIG. 26 may potentially include those linked to a halogenated phenolring via a C—C linkage or bond (with the caveat that for some compounds,the C—C bond may become cleaved). According to these embodiments wherecleavage does not occur, the starting compound would have the chemicalstructure of the drug compound except that a hydroxyl group (—OH) on thephenol ring of the drug product of the reaction is replaced with thehalogen (X) in the starting compound. Compounds of the present inventionaccording to Formula 26 may be cloaked (i.e., their activity is masked)but may become converted into bioactive products as a result of thedehalogenation reaction in the presence of FROS in the targeted tissueor cells. Compounds according to these embodiments may include modifiedthyroid hormones, such as a halogenated thyroid hormone, that areconverted into thyroid hormone by dehalogenation.

Alternatively, compounds of the present invention according to Formula26 may include compounds that consume oxidants and/or free radicalsduring the dehalogenation reaction, but which generally do not form abioactive compound or drug. In other words, the product of thedehalogenation reaction may be partially, mostly, or completelybiologically or medically inert. As an example, such compounds mayinclude diiodotyrosine (DIT). However, some compounds according to theseembodiments may form products that function as an anti-oxidant and/orfree radical scavenger in a subsequent or additional reaction(s).

FIG. 27 provides an example of an embodiment of the present invention(according to the general Formula 26 in FIG. 26) for the targeteddelivery of a drug, L-DOPA, to targeted cells or tissues, which may beuseful for the treatment of Parkinson's disease. According to theseembodiments, a mono-halogenated tyrosine compound (e.g.,monoiodo-tyrosine or MIT, such as 3-iodo-4-hydroxy-L-phenylalanine or3-iodo-tyrosine) may be taken by or administered to an individual andconverted to L-DOPA in a targeted tissue of the individual in responseto free radicals and/or oxidative agents present in the targeted tissue.The C—C bond between the halogenated phenol ring and the remainder ofthe mono-halogenated tyrosine molecule is not cleaved during thedehalogenation reaction triggered by the presence of free radicalsand/or oxidative agents in the targeted tissue. Therefore, the productof the reaction, L-DOPA, may be delivered to targeted sites within thebody of the individual due to elevated levels of free radicals and/oroxidative agents present at these sites without the production of abenzenetriol or like product. According to this embodiment, X is ahalogen in the ortho position relative to a hydroxyl group (—OH) on thephenol ring (i.e., X is a halogen that is bonded to a carbon that isadjacent to a carbon bonded to a hydroxyl group (—OH) on the phenolring). The halogen X may be selected from either iodine (I) or bromine(Br), but generally may not include fluorine (F) or chlorine (Cl).

Another example embodiment of the present invention may include acompound similar to the mono-halogenated tyrosine compound shown in FIG.27 but with the positioning of the halogen X and hydroxyl group reversed(e.g., 3-hydroxy-4-iodo-L-phenylalanine). This compound would also beconverted to L-DOPA by dehalogenation in the presence of free radicalsand/or oxidative agents. According to these embodiments, the L-DOPAproduct of these reactions may also be further converted into dopaminevia the activity of a DOPA decarboxylase enzyme present in the targetedtissue.

According to other embodiments, a dehalogenation reaction withoutcleavage may also be used to generate dopamine directly. For example, amono-halogenated tyramine with the halogen at the 3-position, such as3-iodo-tyramine, which is like dopamine but with a halogen, such asiodine, in place of one of the hydroxyl groups, may be used as astarting compound. In the presence of FROS, a 3-iodo-tyramine startingcompound may be converted by dehalogenation without cleavage intodopamine. Similarly, as described above in reference to L-DOPA, thepositioning of the halogen and the hydroxyl group may be reversedrelative to the mono-halogenated tyramine compound. Such a3-hydroxy-4-iodo-phenethylamine compound may also be used to generatedopamine by dehalogenation without cleavage in the presence of FROS.Much like the MIT and 3-hydroxy-4-iodo-L-phenylalanine compounds, the3-iodotyramine and 3-hydroxy-4-iodo-phenethylamine compounds may be usedto treat Parkinson's disease by releasing or generating dopamine in atargeted tissue of the brain.

According to other embodiments of the present invention, reverse T3 orrT3 (i.e., 3,3′,5′-triiodothyronine) may also be used instead of MIT toform L-DOPA in the body. As described above in connection with FIG. 22,reverse T3 is converted to MIT via a dehalogenation and cleavagereaction. However, the MIT produced by this reaction may then besubsequently converted to L-DOPA by an oxidative de-iodination reactionwithout cleavage as described immediately above in reference to FIG. 27.Therefore, rT3 may be converted to L-DOPA through a two-step processaccording to these two reactions in combination. As also describedabove, the L-DOPA once formed may then be converted into dopamine in thetargeted tissue, such as by endogenous enzymes. Reverse T3 has nomeasurable thyroid hormone activity and is believed to be generallyinert unless it is converted into other compounds. Therefore, theinertness of rT3 allows it to be taken by or administered to anindividual with little concern for cross-reactivity or side effectsexcept by its downstream products (i.e., particularly L-DOPA ordopamine). Accordingly, compositions of the present invention mayfurther include those comprising MIT and/or reverse T3 that may be usedfor the treatment of disease, such as Parkinson's disease. Like themonoiodo-tyrosine (MIT) compound in FIG. 24 (or themonoiodo-phenylalanine alternative), reverse T3 is able to moreeffectively cross the blood-brain barrier (BBB) relative to L-DOPA dueto the presence of the iodines.

Similarly as described above for halogenated phenols linked to drugcompounds by cleavable linkages, these halogenated phenol compounds withnon-cleavable linkages in FIGS. 26 and 27 have the potential ofproviding improved targeted drug delivery to sites of disease and/orinflammation, increased stability, sustained release, and/or maskedbioactivity in non-targeted tissues compared to existing therapies. Inthe case of the monoiodotyrosine compound in FIG. 27, for example, thepresence of the halogen (e.g., iodine) on the phenol ring effectivelyblocks the ability of DOPA decarboxylase to recognize this compound. Asa result, the ability of monoiodotyrosine to be converted into dopamineis masked or blocked until it is converted into L-DOPA by thedehalogenation reaction in a targeted tissue due to the presence of freeradicals and/or oxidative agents. In addition, much like the halogenatedphenol compounds described above with cleavable linkages to drugcompound(s), potential CNS drug compounds according to theseembodiments, such as monoiodo-tyrosine or 3-hydroxy-4-iodo phenylalanine(or the 3-iodotyramine and 3-hydroxy-4-iodo-phenethylamine compounds),may also have the benefit of increased hydrophobicity (due to presenceof the halogen) leading to improved ability to cross the blood-brainbarrier to exert their effects in the brain due to the presence of thehalogen on the phenol ring. These embodiments may provide furtherbenefits as a result of its simpler design and fewer products of thedehalogenation reaction (e.g., no benzenetriol-based orhydroxyhydroquinone-based compounds are produced) relative to thehalogenated phenol compounds with cleavable linkages described above.

Embodiments of the present invention may further include compositionscomprising a stereoisomer, such as a D- and L-isomer, of any of thecompounds and formulas, or portions thereof, described herein inconnection with FIGS. 1-29 that are asymmetric or chiral.

According to some embodiments, any of the compositions, compounds andformulas of the present invention, and combinations thereof, such asthose in FIGS. 1 through 29, including any salt, solvate, or hydratethereof, may be formulated as pharmaceutical compositions in combinationwith a pharmaceutically acceptable carrier. Such pharmaceuticalembodiments of the present invention may be formulated as pharmaceuticalcompositions comprising a therapeutically effective (or desired) amountof any of the compounds or formulas as described herein, such as inFIGS. 1 through 29, or a salt, solvate, or hydrate thereof, incombination with a pharmaceutically acceptable carrier.

For the various embodiments of compounds of the present inventionformulated as pharmaceutical compositions in combination with apharmaceutically acceptable carrier, examples of pharmaceuticallyacceptable carriers and other suitable additives and adjuvants forpharmaceutical compositions that may be used in combination withembodiments of compounds of the present invention for taking by, oradministration, providing or giving to, an individual, subject, orpatient include those known to those skilled in the pharmacological orpharmaceutical arts. As used herein, such pharmaceutically acceptablecarriers may be either liquid or solid and may include solvents,dispersion media, coatings, surfactants, antioxidants, preservatives(e.g., antibacterial agents, antifungal agents), isotonic agents,absorption delaying agents, salts, preservatives, drugs, drugstabilizers, gels, binders, excipients, fillers, diluents,disintegration agents, lubricants, sweetening agents, flavoring agents,dyes, glidants, wetting agents, etc., and combinations thereof. For adescription of suitable pharmaceutical compositions, carriers, etc. thatmay be used in formulating pharmaceutical compositions and compounds ofthe present invention, see, for example, Remington, The Science andPractice of Pharmacy, (University of the Sciences in Philadelphia, 21sted., Lippincott Williams & Wilkins Co., 2005). See also, for example,U.S. Pat. Nos. 7,390,808, 7,354,928, 7,348,325, 7,326,713, and 7,282,504(the contents and disclosures of which are incorporated herein byreference) for a description of suitable pharmaceutical compositions,carriers, etc., that may be used with pharmaceutical compositions andcompounds of the present invention.

Except insofar as any conventional pharmaceutical carrier isincompatible with embodiments of the compounds or compositions of thepresent invention, their potential use in pharmaceutical compositions ofthe present invention is contemplated. Embodiments of the pharmaceuticalcompositions and formulations of the present invention may utilizedifferent types of carriers depending on whether they are to be taken oradministered in solid, liquid or aerosol form and whether they need tobe sterile for certain routes of administration, such as local orsystemic injection or infusion.

For embodiments of compounds of the present invention formulated aspharmaceutical compositions in combination with a pharmaceuticallyacceptable carrier, examples of pharmaceutically acceptable carriers mayfurther include other delivery systems and reagents known in the art.Where appropriate, such delivery systems or reagents may include, forexample, liposomes, microparticles or nanoparticles, microcapsules,emulsions, polymers, etc., or any combination thereof. Liposomes may becoated with opsonization-inhibiting moieties or molecules (e.g., PEG) toavoid detection by the immune system and may be specifically formulatedand/or associated with other molecules, antibodies, or conjugates toimprove delivery, intake, and/or specificity into specific tissues orcells. See, e.g., Szoka et al., “Comparative properties and methods ofpreparation of lipid vesicles (liposomes),” Ann. Rev. Biophys. Bioeng.,9:467 (1980); Immordino, M. L., “Stealth liposomes: review of the basicscience, rationale, and clinical applications, existing and potential,”Int. J Nanomedicine 1(3):297-315 (2006); Samad, A., “Liposomal DrugDelivery Systems: An Update Review,” Current Drug Delivery 4(4): 297-305(2007); and Gregoriadis, G., Liposome Technology (Three-Volume Set),(3^(rd) Ed., Informa Healthcare, 2006), the contents and disclosures ofwhich are incorporated herein by reference in their entirety. See also,e.g., U.S. Pat. Nos. 4,501,728, 4,837,028, and 5,019,369, the contentsand disclosures of which are incorporated herein by reference.

A therapeutically effective amount of a compound may include an amountof the compound effective to achieve a desired result or purpose ortherapeutic benefit, including the effective treatment, alleviation,abatement, inhibition, prevention, management, etc., of inflammation,disease, and/or oxidative or free radical stress in an individual, orany symptoms associated with inflammation, disease, and/or oxidative orfree radical stress. Determination of a therapeutically effective amountof a compound may be carried out in a manner known to those skilled inthe art. For example, a therapeutically effective amount may compriseany appropriate dosage depending on the exigencies of a given situationincluding the age, gender, weight, etc. of the individual to be treated.To determine an amount or dosage that is appropriate for taking by oradministration to an individual, subject, or patient, treatment dosagesmay be titrated to optimize safety and effectiveness. Lower thanexpected dosages may be administered first to an individual, subject, orpatient, and these dosages may then be titrated upward until atherapeutically effective and safe concentration amount (or apotentially unsafe concentration or amount) is reached.

A therapeutically effective amount or dosage for a particular compoundof the present invention may be determined or predicted from empiricalevidence. Dosages or concentrations tested in vitro for embodiments ofcompounds of the present invention may provide useful guidance indetermining therapeutically effective and appropriate amounts for invivo administration. For example, a therapeutically effective dose of acompound according to embodiments of the present invention may beestimated initially from values obtained from any cell culture or invitro assay. Such values may be used, for example, to translate intoappropriate amounts for use in animal testing or for clinical trials inhumans. Determining an appropriate dosage for an embodiment of acompound of the present invention may be discerned from any and/or allinformation or data available from any assay or experiment performed.

Animal testing of predicted dosages for compounds of the presentinvention may provide additional indication of a proper dosage ortherapeutically effective amount for other types of animals, includinghumans. For example, a proper dosage or therapeutically effective amountof a compound of the present invention may be deduced from an amountthat results in a circulating concentration of the compound in a testanimal that roughly approximates concentrations shown to be effectiveaccording to cell culture and/or in vitro assays. Test animals may beused initially to determine the effectiveness and/or safety at such acirculating concentration or to determine or extrapolate a useful dosageor therapeutically effective amount of the compound for other animals,such as humans.

Toxicity and therapeutic efficacy of such a compound may be determinedor predicted from any standard pharmaceutical procedures based on anycell culture or in vivo data. For example, an LD₅₀ value (i.e., doselethal in 50% of the population) and an ED₅₀ value (the dosetherapeutically effective in 50% of subjects according to a certaincriteria) may be determined for a given compound in an animal testsubject, and the ratio of LD₅₀/ED₅₀ may be expressed as a therapeuticindex. Compounds that exhibit a high therapeutic index may indicate thathigher concentrations of the compound are safe and non-toxic and/or thatlower doses may be efficacious in an individual, subject, or patient.However, a lower therapeutic index may indicate that only lower (andperhaps ineffective) concentrations of a compound may be acceptable interms of safety. The level of a compound in the blood or plasma of anindividual, subject, or patient may be measured or monitored by anyknown technique including, for example, high performance liquidchromatography. In most cases, an appropriate dosage or therapeuticallyeffective amount of a compound will be a balance of factors mainlyincluding efficacy and safety. Furthermore, a therapeutically effectiveamount of a compound may vary depending on the particular compositionand mode of administration.

According to another broad aspect of the present invention, methods areprovided for effectively treating, alleviating, inhibiting, preventing,managing, etc., inflammation, disease, and/or oxidative or free radicalstress in an individual, subject, or patient, or any symptoms associatedwith inflammation, disease, and/or oxidative or free radical stress inan individual, subject, or patient, by a composition or compound of thepresent invention, or a salt, solvate, or hydrate thereof administeredto, or taken by, the individual, subject, or patient. A compound of thepresent invention may be administered to an individual, subject, orpatient having or experiencing (or suspected of having or experiencing)inflammation, disease, and/or oxidative or free radical stress, or anysymptoms associated with inflammation, disease, and/or oxidative or freeradical stress. Indeed, a compound of the present invention may be takenby, or administered, provided or given to, an individual, subject, orpatient having or experiencing (or suspected of having or experiencing)a condition, disease or inflammation associated with elevated levels ofFROS.

These methods of treatment embodiments may comprise taking, deliveringor administering a composition comprising one or more of the compoundsof the present invention, such as those in FIGS. 1 through 27, or asalt, solvate, or hydrate thereof, perhaps in combination with apharmaceutically acceptable carrier. Such a method may comprise atherapeutically effective amount of the compound taken by oradministered to an individual. A therapeutically effective amount ordosage for a particular compound of the present invention may beadjusted after administering an initial dosage or amount by monitoringprogress against inflammation, disease, and/or oxidative or free radicalstress in an individual, subject, or patient, or against any symptomsassociated with inflammation, disease, and/or oxidative or free radicalstress in an individual, subject, or patient. Although release orformation of the product of the dehalogenation reaction may occurspontaneously in FROS containing tissues, release or formation of theproduct of the dehalogenation reaction may also be induced by externallyapplied radiation to the body of an individual being treated, such asfocused radiation at a particular location(s) within the body of theindividual.

Progress against inflammation, disease, and/or oxidative or free radicalstress, or one or more symptoms thereof, may be monitored or measured interms of efficacy and safety in response to administration of acomposition or compound of the present invention and may be used tomodify subsequent treatments. Progress against inflammation, disease,and/or oxidative or free radical stress, or one or more symptomsthereof, may be monitored or measured by any known pathological orclinical test or procedure for a given disease, including, for example,any known genetic, molecular, or biochemical techniques using tissuebiopsies, blood samples, etc. There are numerous research methods,reagents, and/or diagnostic kits, assays and tools known and availablein the art for measuring or monitoring progress against a disease (e.g.,gene expression, molecular markers, genetic testing, labels, antibodies,karyotyping, chemical detection, etc.). In addition, progress againstdisease may be monitored according to any known or establishedveterinary, medical, and/or pathological technique (e.g., by observationof symptoms, etc.). Although such techniques, assays, reagents, and/ordiagnostic kits are numerous, it is envisioned that any such method,reagent, and/or diagnostic procedure or kit, as well as any known orestablished veterinary, medical, research, and/or pathology technique,may be used to monitor progress against disease. Progress against aparticular disease or condition may be evaluated according to known andavailable methods and diagnostics for that particular disease orcondition as chosen by a qualified physician, veterinarian, or scientistattending to the care or treatment of an individual, subject, or patientbeing treated.

According to embodiments of present compositions, the exact formulation,route of administration, and dosage of a particular compound may bechosen according to the judgment of a skilled scientist, veterinarian,or physician in view of the characteristics and conditions of anindividual, subject or patient. Factors considered in determining anappropriate dosage or therapeutically effective amount for anindividual, subject, or patient in clinical settings may include themanner/route of administration, timing of administration, rate ofexcretion, target site, disease or physiological state, medical history,age, sex, physical characteristics, other medications, etc. This list offactors is illustrative and not exhaustive, and may include any or allfactors which might be considered by a skilled scientist, veterinarian,or physician (as the case may be) in determining an appropriatetreatment. For appropriate considerations and guidance in determining atherapeutically effective amount or dosage as well as appropriateformulations and/or routes of administration, see, e.g., Remington, TheScience and Practice of Pharmacy, (University of the Sciences inPhiladelphia, 21st ed., Lippincott Williams & Wilkins, 2005); andGoodman & Gillman, The Pharmacological Basis of Therapeutics, (11^(th)Edition, McGraw-Hill Professional, 2005).

An appropriate dosage or therapeutically effective amount forembodiments of the compounds or compositions of the present inventionmay be in the range of, for example, from about 0.1 to about 100 mg perkg of body mass per day, from about 0.5 to about 60 mg per kg of bodymass per day, or from about 1.0 to about 40 mg per kg of body mass perday. According to some embodiments, a therapeutically effective amountmay be formulated as a unit dosage amount, which may be in the range offrom about 1.0 to about 500 mg, from about 1.0 to about 250 mg, or fromabout 5.0 to about 150 mg. However, the appropriate dosage ortherapeutically effective amount for embodiments of the compounds orcompositions of the present invention will depend on a consideration ofrelevant factors, including the relative levels of therapeuticeffectiveness and safety, the mode of administration, etc., as well asavailable empirical data about the compound or composition according tothe knowledge and expertise of one skilled in the relevant art.

According to embodiments of compounds of the present inventionformulated as a pharmaceutical composition, such a pharmaceuticalcomposition may be taken or administered in a variety of unit dosageforms depending on the method of administration. For example, unitdosage forms suitable for oral administration may include solid dosageforms, such as powders, granules, tablets, pills, capsules,suppositories, depots, or dragees; or liquid dosage forms, such aselixirs, syrups, suspensions, sprays, gels, lotions, creams, slurries,foams, jellies, ointments, salves, solutions, suspensions, tinctures,and/or emulsions. Because of their ease of administration, tablets andcapsules may be used as an oral dosage unit form when solidpharmaceutical compositions are employed. Pharmaceutical compositionsmay further include time-release or sustained-release formulations. Forparenteral administration, pharmaceutical compositions of the presentinvention may be formulated as sterile solutions, emulsions, and/orsuspensions. Pharmaceutical compositions for topical administration mayfurther include patches (e.g., dermal patches, creams, etc.) or sprays,and pharmaceutical compositions for pulmonary administration may includeaerosols.

According to many embodiments, compounds of the present invention mayinclude a compound comprising a halogenated phenol ring linked to a drugcompound via a cleavable linkage, which may be liberated in a desiredchemical (i.e., FROS-containing) environment. Therefore, methods oftreatment according to some embodiments may include taking by, oradministering, providing or giving to, an individual one or more ofthese compounds of the present invention, such as those in FIGS. 1through 20, (e.g., as a pharmaceutical composition) to any individual,subject, or patient that may otherwise receive the same drug compoundwithout the covalently attached halogenated phenol ring. According toother embodiments, novel compounds of the present invention may alsoinclude modified drug compounds that contain a halogenated phenol ringbut do not contain a cleavable linkage to the phenol ring apart from thehalogen. Such a modified drug compound may be converted without suchcleavage to become the drug compound in a desired chemical environment.Therefore, methods of treatment according to some embodiments mayinclude taking by, or administering, providing or giving to, anindividual one or more of these alternatively modified drug compounds ofthe present invention, such as those in FIGS. 26 and 27, (e.g., as apharmaceutical composition) to any individual, subject, or patient thatmay otherwise receive the same drug compound product formed by theseembodiments in the appropriate chemical (i.e., FROS-containing)environment.

Generally speaking, present methods of treatment will depend on thenature of the drug compound formed linked to the halogenated phenol ringof a starting compound of the present invention (or formed by anon-cleavable starting compound of the present invention). Thus, if aspecific drug compound X is used to treat disease or condition Y in anindividual, then compositions comprising a starting compound of thepresent invention that releases or forms the same drug compound X inFROS tissues (as a result of the dehalogenation reaction) may generallybe administered in the same clinical context(s) that drug compound Xwould be administered.

As an example, L-DOPA is a standard therapy for the treatment ofParkinson's disease. The disease is characterized by motor symptoms, andmay later include cognitive and behavioral problems as well. Thus,according to embodiments of the present invention, a person determinedto have, diagnosed as having, having or suspected of having Parkinson'sdisease, dopamine deficiency, or other neuromuscular disorder orsymptoms may take or be given, provided, or administered apharmaceutical composition comprising one or more of:3-hydroxy-3′-iodo-thyronamine (FIG. 8A), 3-hydroxy-3′-iodo-thyronine(FIG. 8B), reverse T3 (FIG. 22), 3-hydroxy-4-iodo-phenylalanine,mono-iodotyrosine or MIT (FIG. 27), 3-iodotyramine and/or3-hydroxy-4-iodo-phenethylamine. Such pharmaceutical may be administeredorally, such as a tablet, etc., but may also be administeredparenterally, especially if there are digestive issues. For treatment ofParkinson's with L-DOPA, a common dosage may include about 100 mg every3 hours. Accordingly, a dosage amount for embodiments of the presentinvention may be about the same within an order or two of magnitude.However, as with any drug, the precise regimen and dosage will depend ona variety of factors including feedback from treatment according to goodpharmaceutical management of the patient and symptoms. Indeed, somepatients may receive a reduced dose or be excluded from treatment due totoxicity to the drug or extrapyramidal symptoms. As mentioned above,compounds of the present invention may be better able to diffuse acrossthe BBB and/or minimize or eliminate the need for co-treatment withCarbidopa due to targeted delivery.

Another treatment example of the present invention may includedelivering an antibiotic to a site of infection and/or inflammation.Sites of infection may be highly associated with inflammation and highFROS production. Thus, embodiments of the present invention may be usedfor targeted delivery of an antibiotic to a site of infection. Anyantibiotic having a “linkable” substituent for linking to a halogenatedphenol ring may be used as a starting compound. According to theseembodiments, an individual determined to have, diagnosed as having,having or suspected of having an infection may take or be given,provided, or administered a pharmaceutical composition comprising astarting compound of the present invention that will produce or releasean antibiotic in a targeted tissue. For example, such a composition maycomprise Compound 18 (in FIG. 18) for release of penicillin or relatedcompounds.

According to another set of treatment examples of the present invention,a composition comprising a starting compound of the present inventionmay be taken or administered that will produce or release an analgesic(pain reducer) in a targeted tissue. Sites of tissue or bone injury,burns, autoimmunity, bone or joint degeneration, infection, diseaseand/or inflammation may be associated with pain symptoms as well as highlevels of FROS. Thus, embodiments of the present invention may be usedfor targeted delivery of an analgesic to these sites in the body.Accordingly, embodiments of the present invention may include methods oftaking by, or administering, giving or providing to, an individualhaving or experiencing pain or discomfort, a pharmaceutical compositioncomprising a starting compound of the present invention that willproduce or release an analgesic drug in targeted tissues (i.e.,location(s) of pain). As one example embodiment, a compositioncomprising Compound 11A (in FIG. 11A) may be used to produce or releaseacetaminophen at a site of pain, especially for mild pain. According toother example embodiments, a composition comprising Compound 11B (inFIG. 11B) or Compound 11C (in FIG. 11C) may be used to produce orrelease dihydromorphinone (DILAUDID®) or morphine, respectively, at asite of pain, especially for treatment of more severe or extreme pain.

According to another set of treatment examples of the present invention,a composition comprising a starting compound of the present inventionmay be taken or administered, provided or given that will produce orrelease an anti-inflammatory drug in a targeted tissue, which may alsohave analgesic effects. Sites of tissue or bone injury, such as cuts,burns, breaks, etc., autoimmunity, bone or joint degeneration, such asarthritis, etc., infection, and/or disease, such as cancer, etc., may beassociated with inflammation and pain symptoms as well as high levels ofFROS. Thus, embodiments of the present invention may be used fortargeted delivery of an anti-inflammatory/analgesic to such sites in thebody. Accordingly, embodiments of the present invention may includemethods of taking by, or administering, providing or giving to, anindividual having or experiencing inflammation and/or pain ordiscomfort, a pharmaceutical composition comprising a starting compoundof the present invention that will produce or release ananti-inflammatory drug in a target tissue (i.e., at the location ofinflammation). As one example embodiment, a composition comprisingCompound 19A (in FIG. 19A) may be used or administered to produce orrelease aspirin at sites of inflammation and/or pain or discomfort. Asanother example, a composition comprising Compound 19B (in FIG. 19B) maybe used to produce or release naproxen at sites of inflammation and/orpain or discomfort. As yet another example, a composition comprisingCompound 19C (in FIG. 19C) may be used to produce or release ibuprofenat sites of inflammation and/or pain or discomfort to reduce pain,inflammation and/or swelling.

In a related treatment example, particularly when a more potentanti-inflammatory effect is desired, a pharmaceutical compositioncomprising a starting compound of the present invention that willproduce or release a steroidal anti-inflammatory, such as cortisol orcortisone, may be used. Accordingly, embodiments of the presentinvention may include methods of taking by, or administering, providingor giving to, an individual having or experiencing inflammation and/orpain or discomfort, a pharmaceutical composition comprising a startingcompound of the present invention that will produce or release asteroidal anti-inflammatory drug in a target tissue (i.e., atlocation(s) of inflammation, that may be). For example, a compositioncomprising Compound 13 (in FIG. 13) may be used to produce or releasecortisone at sites of inflammation. Again, these embodiments may be usedto deliver the steroidal anti-inflammatory to high FROS-producing sitesin the body, such as sites of tissue injury, autoimmunity, bone or jointdegeneration, such as arthritis, etc., infection, and/or disease, suchas cancer, etc., that may be associated with inflammation and/orswelling of tissue.

As yet another treatment example of the present invention, apharmaceutical composition comprising a starting compound that willproduce or release an anti-tumor, chemotherapy and/or cytotoxic compoundor agent at a cancerous or tumor site. Sites of cancerous cells, tissuesor tumors are often associated with inflammation and high FROS. Thus,compositions and methods of the present invention may be used fortargeted delivery of such compounds or agents to cancerous cells,tissues or tumors. Accordingly, embodiments of the present invention mayinclude methods of taking by, or administering, providing or giving to,an individual determined or diagnosed as having, having or suspected ofhaving cancer, a pharmaceutical composition comprising a startingcompound of the present invention that will produce or release achemotherapeutic, anti-tumor or cytotoxic drug at or in a target tissue(i.e., at sites or locations of cancerous cells or tissues and/ortumors). As one example embodiment, a composition comprising Compound 16(in FIG. 16) may be used or administered to produce or releasemethotrexate in or near cancerous tissues or cells and/or tumor sites.As another example for targeted delivery of a chemotherapeutic agent tosites of cancerous cells or tissue and/or tumors, such a composition mayalternatively comprise Compound 14 (in FIG. 14) for targeted delivery of5-iodo-uracil to cancerous or tumor sites in the body.

Another treatment example of the present invention may include methodsof administering or delivering serotonin to an individual. Deficientlevels of serotonin are associated with psychological conditions, suchas depression, anxiety, and some personality disorders. Serotoninreuptake inhibitors (SRIs) or selective serotonin reuptake inhibitors(SSRIs) are existing therapies. It is theorized that serotonindeficiency may be related to ischemic conditions and/or mini-strokeevents at key locations in the brain that can lead to production ofFROS, which can damage cells or tissue and impair function. Also,regions of the brain responsible for production of serotonin, such asthe Raphe nuclei, may be damaged by FROS. Accordingly, embodiments ofthe present invention may include methods of taking by, oradministering, providing or giving to, a person determined to have,diagnosed as having, having or suspected of having a serotonindeficiency, depression, anxiety or like symptoms, a pharmaceuticalcomposition comprising a starting compound of the present invention thatwill produce or release serotonin in a targeted tissue. For example, acomposition comprising Compound 10 (in FIG. 10) may be administered.Compounds of the present invention may also be given or administered inaddition to, or in conjunction with, standard therapies, such asserotonin, SRIs and/or SSRIs. Again, due to the presence of thehalogenated phenol ring, the compound will diffuse across the BBB andenter the brain.

As yet another example, embodiments of the present invention may includemethods of administering a pharmaceutical composition comprising astarting compound of the present invention that will produce or releaseestradiol or estrogen in a targeted tissue. For example, such acomposition may comprise Compound 9 (in FIG. 9). Such a composition maybe taken by, or administered, provided or given to, postmenopausal womenhaving an estrogen deficiency. Tissue or cells that are estrogendependent may be experiencing cellular stress, which could result inhigh FROS. Such compositions may also be used to target and treat sometypes of cancers or tumors that are inhibited by or sensitive toestrogen or its derivatives.

According to additional embodiments, novel compounds of the presentinvention may also include anti-inflammatory, anti-oxidant, and/or freeradical scavenging compounds comprising a halogenated phenol ring with acleavable linkage, but which may not release or produce a drug compoundapart from its anti-inflammatory, anti-oxidant, and/or free radicalscavenging ability. Such compounds may remove, consume or depleteoxidizing agents and/or free radicals from an in vivo environment ortargeted tissue, which may be associated with inflammation and/ordisease. Therefore, methods of treatment according to these additionalembodiments may include taking by, or administering, providing or givingto, an individual one or more of these anti-inflammatory, anti-oxidant,and/or free radical scavenging compounds of the present invention, suchas those in FIGS. 21 through 25, (e.g., as a pharmaceutical composition)to any individual, subject, or patient in need thereof.

According to these embodiments, such compositions comprising startingcompounds represented in FIGS. 21-25 may be taken by, or administered,given or provided to, someone experiencing heightened levels of FROSand/or inflammation, either systemically or in a particular tissue, toscavenge, quench or consume FROS and thus protect cells and tissues ofthe body from damage. Such heightened levels of FROS and/or inflammationmay be associated with a variety of diseases or conditions characterizedby inflammation, immune reactions and/or altered metabolism, such asautoimmune conditions, arthritis, multiple sclerosis (MS), ischemicbowel disease, retrolental fibroplasias (RLF), ischemia and/orreperfusion associated with myocardial infarct or stroke, cachexia,sepsis, etc. Thus, in addition to providing a protective function, theseantioxidant and/or FROS scavenging compositions may also be used toreduce, treat or alleviate symptoms associated with these diseases orconditions. These compositions may be used to treat or reduce symptomsassociated with disease, such as cancer, etc., in addition to, or apartfrom, treatment with a drug. By reducing FROS, protecting cells andtissues and/or reducing inflammation, these compositions may be able toslow, contain or impede disease progression and/or mask its symptoms,possibly as an effective “cure,” in some cases. By “mopping up” FROSpresent in a tissue, normal cells may be better able to survive andfunction normally, and stem cells may be able to migrate to affectedareas and/or proliferate and differentiate to repair damaged tissue.

In addition, these antioxidant and/or FROS scavenging compositionscomprising starting compounds in FIGS. 21-25 may be used or administeredinstead for preventative or prophylactic purposes, such as in normal orhealthy individuals. An individual could take a composition comprisingone of more of these compounds on a regular basis, much like a dailyvitamin, as a means of general protection against cell or tissue damageresulting from FROS. Such regular preventative use of these compositionsmay minimize or avoid chances for disease, improve quality of life andvigor, as well as provide an anti-aging benefit. In many cases, thecause of disease as well as its progression and symptoms may be mediatedby FROS generation in tissues, which may result in wear-and-tear overtime and lead to tissue damage, impaired tissue function and possiblycell death. Thus, compositions of the present invention may be useful inprotecting these cells and tissues over time. For example, compositionsof the present invention may be used to protect cells and tissue inhighly metabolic regions of the brain, such as the substantia nigra,from insults caused by high levels of FROS to avoid tissue damage anddisease and improve cognitive function.

Embodiments of the present invention may also include compositions, suchas pharmaceutical compositions, comprising any compound linked to ahalogenated phenol ring described herein that produces a colored ordetectable product(s) in the presence of FROS. Such compounds mayinclude, for example, any indigogenic compound represented in FIGS. 28and 29. Methods of taking by, or administering, providing or giving to,an individual or patient any such compositions are further provided,wherein the detectable product(s) of the dehalogenation reaction maythen be detected or measured systemically, in bodily fluids, or in aspecific tissue(s) of the individual or patient in which the detectablecompound is formed (i.e., in situ or by taking a sample as part of anassay) for diagnostic purposes (see below). If the starting compoundadministered is any compound represented by FIGS. 1-25, 28 and 29, thenthe product that may be detected or measured may include abenzenetriol-based or benzenetetrol-based product, as a quinone and/orphenolic species, or a halide. In the case of detection or measurementof a halide, the halide may be produced by any of the starting compoundsrepresented by FIGS. 1-29. As discussed further below, thebenzenetriol-based or benzenetetrol-based product(s) may be detected ormeasured, for example, by absorbance, nuclear magnetic resonance (NMR),mass spectrometry (MS), chemical test, etc. For absorbance, thebenzenetriol-based or benzenetetrol-based product(s) may be detected ormeasured by a spectrophotometer at wavelength absorptions in the UVrange, and in the color range for quinone species. Halides, such asiodide, may be detected or measured by known methods. The amount, leveland/or rate of increase of these detectable products may be indicativeof the amount or level of FROS systemically or in a particular tissue,which may indicate the existence and stage of disease or inflammation.

In any case, the ability to detect or measure systemic levels of one ormore detectable product(s) of the reaction from a starting compound ofthe present invention by taking a sample from an individual provides auseful tool that may be used as a replacement for detection ofC-reactive protein (CRP) as a measure of general inflammation or FROSload in the body of an individual, which may indicate the presence ofdisease.

Thus, according to embodiments of the present invention, a startingcompound of the present invention may be taken by, or administered,provided or given to, an individual, and product(s) of thedehalogenation reaction (e.g., benzenetriol-based or benzenetetrol-basedproduct(s) in the case of starting compounds in FIGS. 1-25, 28 and 29;and/or halides in the case of starting compounds in FIGS. 1-29) may bedetected or measured either from a sample, such as blood, urine, ortissue biopsy. Such a sample may be further processed to isolate,purify, concentrate, etc., the detectable product from the sample priorto detection or measurement.

As described further below in connection with FIGS. 28 and 29,indigogenic compounds are cleaved by the dehalogenation reaction to formvisibly colored indigo-like products in the presence of FROS. Theindigo-like compounds formed by these reactions may also generally havehigher residence time where formed (i.e., in high FROS tissues),allowing for their detection in situ as an indication of sites ofinflammation and/or disease. However, some amount of indigo-like product(once formed) may flow away from its site of formation, which may bedetected or measured systemically from a sample. Indeed, the indigo-likecompound is preferably not permanent in the tissue and will clear fromthe tissue as some rate. As further explained below, other products ofthe reaction without residence time in the tissue may also be detectedor measured systemically for diagnostic purposes. As described above,according to some embodiments, any compound of the present invention,such as those represented in FIGS. 1-29, may be administered, and theamount of product (e.g., benzenetriol-based product, benzenetetrol-basedproduct and/or halide) may be detected and/or measured.

Accordingly, embodiments of the present invention include methods oftaking by, or administering, providing or giving to, an individual acomposition comprising an indigogenic compound of the present invention,such as a starting compound represented in FIGS. 28 and 29, to anindividual and detecting the formation of an indigo-like product. Inthose situations where the indigo-like product is detected in situ dueto its residence time in tissues where it is formed, the product may bedetected visually (in the case of a distinguishably colored product;e.g., FIG. 29A) or by radiography or X-ray imaging (due to thehalogenated indigo-like compound being radio-opaque; e.g., FIGS. 29B and29C). In the case of distinguishably colored indigo-like products, theproduct may be directly visualized, which may provide assistance, forexample, during a surgical operation. In some cases, an intermediate ofthe dehalogenation reaction involving an indigogenic compound may bevisualized by fluorescence caused by UV light excitation.

In each of the in situ contexts, the indigo-like product formed by thereaction from a starting compound of the present invention may bedetected to determine sites of disease or cancer, such as ductalcarcinoma, etc. In addition to cancer or tumors, FROS sites of formationand residence of an indigo-like product may also indicate sites ofinfection or other disease. In the case of CNS conditions or diseases,localization of an indigo-like product may provide information aboutaffected areas for diagnosis. Different areas of the brain areassociated with different cognitive and neurochemical functions. Thus,correlation between (i) behavioral symptoms and patient history and (ii)localization of FROS-producing indigo-like products to specific regionsof the brain may provide strong evidence for a causal connection. Forexample, the substantia nigra (SN) of the brain is highly metabolic withhigh FROS in patients with Alzheimer's disease or dementia, whichaffects the dopamine tracts in the SN. The frontal lobe is associatedwith executive and analytical functions, which may also be affected indementia, and the temporal lobes are associated with memory and may beaffected with memory loss. The complementarity of disease detection anddrug delivery (plus FROS scavenging) by the same chemical reactionallows for targeted treatments according to embodiments of the presentinvention to match sites of detection. Following detection, FROSscavengers may be effective at protecting these highly metabolic tissuesfrom cellular and tissue damage to improve their function and reducedisease symptoms.

Even though indigo-like products of the reaction may have some amount ofresidence time in the tissue where they are formed, they do graduallyand eventually diffuse away from their site of formation. Thus, theseindigo-like products may be further detected or measured by othermethods, such as absorbance, NMR, etc., using a sample taken from theindividual.

Another method for diagnosis is the detection or measurement of ¹³Ccontaining products of the reaction from starting compounds containingthis stable isotope in place of carbon 12. The presence of this stableisotope provides a basis for distinguishable detection of the product.Following its administration, such a product may be detected or measuredby NMR or MS in the case of detection or measurement in a sample. Suchdetection may provide the same information as described above for otherdetectable products, such as high levels of FROS systemically or in aparticular tissue, which may indicate disease and/or inflammation. Giventhat the ¹³C-containing product may be detected by NMR, it is theorizedthat magnetic resonance imaging (MRI) might potentially be used todetect localization of a detectable product in situ from a ¹³Ccontaining indigogenic compound. However, further work is needed todevelop this technology.

Embodiments of the present invention may further include methods oftaking by, or administering, providing or giving to, an individualsimilar indigogenic compound(s) containing radioactive isotopes (seebelow), which may be converted in an appropriate chemical (i.e.,FROS-containing) environment (i.e., in an inflamed and/or diseasedtarget tissue) to form a compound having a higher residence time whereformed to preferentially irradiate such target tissue. Thus, methods oftreatment according to some embodiments may include taking,administering, providing or giving a composition, such as apharmaceutical composition, comprising a halogenated phenol linkedindigogenic compound containing a radioactive isotope, such as accordingto the compounds or formulas 28 and 29 represented in FIGS. 28 and 29,to an individual, subject, or patient in need thereof. For example, suchradioactive compounds of the present invention may be used to treatcancerous tissues, such as a tumor, and may be administered to a personhaving a cancerous tumor to locally irradiate the tumor due to itstargeted delivery and prolonged residence time in these tissues.

According to embodiments of the present invention, whether fortherapeutic, diagnostic or combined purposes, compositions and compoundsof the present invention may be suitably administered by or given orprovided for any known mode or route of administration. Such mode orroute of administration may depend on the particular compound and/orcondition to be treated and may be chosen to maximize delivery of acompound of the present invention to a desired target site in the bodyof an individual, subject, or patient. Pharmaceutical compositions andcompounds may be administered in a number of ways, including anysuitable enteral, parenteral, topical, or local mode or route, dependingon whether local or systemic treatment is preferred and/or the specificarea to be treated. Suitable enteral routes for administration mayinclude oral, rectal, intestinal, and gastric. Suitable parenteralroutes may include intravascular routes, such as intravenous (bolus andinfusion), intrarterial, and intracardiac; mucosal routes, such astransmucosal (e.g., insufflation), sublingual, buccal, intranasal,pulmonary (e.g., inhalation), and vaginal; intracranial; intraocular;intrathecal; intraperitoneal; intramuscular; intradermal; subcutaneous;intramedullary; or intraosseus. Embodiments of the pharmaceuticalcompositions of the present invention may be further administered viatopical or transdermal routes as well as by local injection at a desiredsite of action, including peri- and intra-tissue injections, such as ator near a site of disease and/or inflammation in the body of anindividual, subject, or patient.

Compounds or compositions according to embodiments of the presentinvention may be administered for therapeutic and/or diagnostic purposeseither as a single dose or as part of a dosage regimen. A dosage regimenmay be adjusted to provide an optimum therapeutic response or diagnosticmeasurement. For example, several different doses may be administereddaily or doses may be proportionally reduced as indicated by theexigencies of a therapeutic situation. By administering an embodiment ofa compound or composition of the present invention as part of a dosageregimen, circulating concentrations may be allowed to reach a desiredequilibrium concentration for a compound through a series of doses. Forconvenience, a predetermined total daily dosage may be divided andadministered in portions during the day as required. The compounds maybe administered according to a dosage regimen of from about 1 to about 5times per day, for example, 1, 2 or 3 times a day.

According to a broad aspect of the present invention introduced above,diagnostic compounds or compositions forming detectable product(s) as aresult of the dehalogenation reaction, along with diagnostic methods ofusing the same, are provided for the indirect detection, indicationand/or measurement of FROS present systemically or in a particulartissue. Such detection or measurement of these products may serve as anindication of specific sites and/or systemic levels of FROS in the bodyof an individual, which may be an indication of inflammation, disease orpathology systemically or in a particular location or tissue. Theseembodiments may be based on compounds that form a colored or otherwisedetectable product(s) upon exposure to an oxidative and/or free radical(FROS) containing environment, which may accompany disease orinflammation, and the amount of colored or otherwise detectable productmay correlate or relate to the degree or level of oxidants and/or freeradicals systemically or in a tissue, which may also indicate the stageor advancement of a disease.

According to some embodiments, the detectable product may include acleavage product of the dehalogenation reaction that is detectable dueto its properties or interaction with light or other electromagneticradiation. For example, the detectable product may include a quinone orphenolic species formed by the dehalogenation and cleavage reaction froma variety of compounds of the present invention. For example, thedetectable product may include a quinone, hydroquinone,hydroxyhydroquinone, benzenetriol-based or bezenetetrol-based product ofthe reaction as discussed further herein that may be produced fromdehalogenation and cleavage of any of the compounds in FIGS. 1-25, 28and 29 as described above, or from a thyroid hormone or aniodo-thyronine compound. Any of these compounds may be administered tothe body of an individual, and the amount of the detectable product maybe measured from a sample or biopsy taken from the individual. For anyof these in vitro detection or diagnostic embodiments, a “sample” (or“test sample”) from an individual may include both (i) a sample takenfrom an individual, as well as (ii) any sample derived therefrom byfurther processing, such as purification, concentration, etc. The term“from” in this sense, means directly or indirectly from the individual.A “sample” (or “test sample”) from an individual may further include asample produced by processing of a biopsy taken from the individual. Theterm “processing” means to perform any chemical procedure or techniqueto alter the sample and improve detection of a detectable product in asample produced thereby.

Thus, detection of the detectable product may be used as an indicationof the amount, level or degree of oxidants and/or free radicals (FROS)present systemically or in a particular tissue. The administeredcompound may generally (or preferably) be one that does not contain orgive rise to a bioactive drug compound since the administered compoundwould be used in these instances primarily for production of thedetectable product. However, the administered compound may include aFROS scavenger and/or anti-oxidant or anti-inflammatory agent. Indeed,the compound may serve a dual role as a FROS scavenger and a diagnosticcompound that gives rise to a detectable product. Alternatively, it isalso proposed that a compound containing a drug compound could be usedsimultaneously for diagnostic purposes with any incidental production ofa detectable product detected in conjunction with treatment.

Quinones are uniquely colored and may thus be detected or measured byspectrophotometric methods of absorption, etc., at particular EM orlight wavelengths or within ranges of EM or light wavelengths, orpossibly by other methods, such as mass spectrometry (MS), nuclearmagnetic resonance (NMR), chemical test, etc. For example, the productsof the dehalogenation reaction may be detected or measured in terms oftheir characteristic peaks by NMR spectroscopy. The benzenetriol-basedor benzenetetrol-based products of the dehalogenation reaction mayresonate between (i) a phenolic or hydroxyl-form (or tautomer) and (ii)a keto-form (or tautomer) (i.e., as a quinone) in an equilibrium, whichmay be affected by an oxidative or reductive environment (i.e.,affecting its oxidation state). Thus, both the phenolic and quinonespecies may potentially be detected or measured as an indication ofFROS. A detectable product of the present invention may have a“hydroxy-quinone structure” including either or both, or any combinationof, the phenolic and/or quinone species of a detectable product formedas a result of a dehalogenation and cleavage reaction from a startingcompound of the present invention. A “hydroxy-quinone structure” furtherincludes a detectable product having any combination of the alternativeketo and hydroxyl groups at different sites on the detectable product(especially in the case of a detectable product having an intermediateor incomplete oxidation state). Although the body may have a tendency toreduce these structures to their more reduced form, a benzenetriol-basedor benzenetetrol-based product formed from a starting compound of thepresent invention that has a “hydroxy-quinone structure” would includeany collection of these products having any combination of keto and/orhydroxyl groups at each site (i.e., at each site where the hydroxylgroups of the detectable product would be located in its fully reducedform).

Phenolic species may be generally measured by absorbance at UVwavelengths, such as in a range from about 275 nm to about 285 nm. Anyquinone species may also be detected or measured by UV absorbance withinthis same wavelength range. However, quinone species may also bedetected or measured by visible coloration and by absorbance of lightwithin visible color wavelength ranges. However, the precise range ofwavelengths of absorbance within the visible light spectrum (and/or thecoloration of the product for direct detection) will depend on the exactchemical formula of the quinone species, which will depend on thestarting compound of the present invention.

Since the quinone species may be differentially detected within avisible color range, the phenolic and quinone species may be separatelydetected and/or measured, and their relative amounts may be expressed asa ratio as a method for improved accuracy and/or standardization. As analternative method to improve accuracy and/or standardization, theamount of benzentriol-based or benzenetetrol-based products of thereaction in either the phenolic or quinone form may be compared againsta control or in relation to a series of different titrated amounts of anadministered starting compound.

Regardless of the detection method, however, the quinone and/or phenolicproducts of the dehalogenation reaction may be first concentrated,purified, isolated, etc., from a sample, such as blood, sputum or urine,or tissue biopsy according to any known technique(s), or combinationsthereof, such as by solvent extraction (e.g., separation into an organicphase), chromatography, etc., prior to measurement. In the case ofblood, the hemoglobin and/or red blood cell fraction (and possibly allcellular components) may be removed from the sample by any known method(e.g., centrifugation, etc.). The benzenetriol-based compound andbenzenetetrol-based (i.e., phenolic) compounds may be relatively moresoluble in water compared to the quinone species. Thus, phase separationmay be used not only to isolate, purify or concentrate the product, butpossibly also to selectively separate the species. One confoundingfactor is that the relative amounts of the phenolic and quinone speciesmay depend on the degree of oxidation or reduction, and resonancebetween these forms may be partial or incomplete. In other words, eachsite containing a hydroxyl or keto group is capable of independentlyresonating. Therefore, a sample, or isolate, purification orconcentration thereof, may be first exposed to either an oxidizing orreducing agent to drive all of these substituents to one or the otherform or species (i.e., a keto or quinone species, or a hydroxyl orphenolic species, respectively) to help standardize the measurement. Asan alternative, embodiments of the present invention further contemplatethe detection or measurement of a halide, such as iodide, produced bythe dehalogenation reaction according to any known method, such as colorindicator detection kits, slow neutron activation assay, NMR, etc., thatis present in a sample taken from an individual as an indication of thelevel of FROS.

According to some embodiments, a product of the dehalogenation reactionmay be detected or measured over a time course following administrationof a starting compound to an individual by taking a series of samplesfrom the individual with the detection profile providing informationabout the level of FROS and/or degree or extent of inflammation ordisease. For example, a time plot showing quick rise in the level of thedetectable product, such as an indigo-like compound, benzenetriol-basedcompound, benzenetetrol-based compound or halide, in a sample followingadministration of a starting compound may be indicative of a high levelof FROS and/or inflammation or disease in the body. In contrast, arelatively slow rise in the level of detectable product might indicatelower levels of FROS and/or inflammation or disease in the body. Thisamount, rate of increase and/or subsequent decay in the time courseexperiment or test may be expressed mathematically as a differentialfunction, tangential line, half-life, area-under-the-curve, etc.

According to embodiments of the present invention as introduced above,the detectable and/or diagnostic product may include an indigo-likecompound that may be formed from two indoxyl, hydroxyl-indolyl orhemi-indigo intermediates due to cleavage of an indigogenic compound(e.g., 5-Iodo-Indolyl-3′-Iodo-4′-Hydroxy Ether compound) in the presenceof FROS (see below). These indigo-like compounds may be visually coloredand/or give off another detectable wavelength(s) of non-visual light.Detection of the light may be aided through the use of an appropriatedevice or instrument, especially for detection of non-visible or lowintensity light. When a measurement of the amount of the detectableproduct in a sample is desired, other methods may be used to furtherconcentrate, purify, isolate, etc., the detectable product, includingthe removal of hemoglobin and/or cells in the case of blood samples, orextraction or removal of cellular and/or extracellular material in thecase of tissues. According to some embodiments, the visible color orother detectable wavelength of light from the indigo-like compound orhydroxyl-indolyl intermediate of the dehalogenation and cleavagereaction (i.e., the reactive indole heterocyclic compound—see below) maybe created or enhanced by its further excitation, exposure orirradiation with light or other electromagnetic radiation, such as lighthaving a particular wavelength(s). For example, an indigogenic compoundlacking halogen substituents may form a classic indigo compound that isvisually detectable due to its blue color. However, thehydroxyl-indolyl, indoxyl or hemi-indigo intermediate resulting from thedehalogenation and cleavage of the indigogenic compound lacking halogensubstituents on the indolyl portion may be detected by fluorescence whenirradiated with, or exposed to, UV light. By administering thisindigogenic compound to the patient prior to surgery, a surgeon may beaided in localizing sites of FROS, which may indicate diseased tissues,during a surgical operation. Indeed, the fluorescence may be generallymore detectable, sensitive and contrasting than visual detection of acolored compound. According to some embodiments, the indigo-likecompound may also (or alternatively) be detected due to its absorbance,scattering, etc., of light or EM radiation, thus causing a reduction inthe amount of transmitted light or EM radiation detected. For example,an indigo-like compound bonded to one or more halogen atoms, such asiodine, may appear to be radio-opaque when resident in intact tissuesand irradiated with, or exposed to, X-rays or other EM radiation.

FIG. 28A provides an exemplary class of indogenic compounds (Formula 28)according to embodiments of the present invention which may be used fordetection or diagnostic purposes. According to these embodiments, anindole heterocyclic portion of the compound (i.e., a hemi-indigocompound), containing variable substituents R₁, R₂, R₃, and R₄, may belinked by an ether linkage to a halogenated phenol ring as part of thecompound of the present invention. X is a halogen in the ortho positionrelative to a hydroxyl group (—OH) on the phenol ring (i.e., X is ahalogen that is bonded to a carbon that is adjacent to a carbon bondedto a hydroxyl group (—OH) on the phenol ring). The halogen X may beselected from either iodine (I) or bromine (Br), but generally may notinclude fluorine (F) or chlorine (Cl). According to these embodiments,the ether linkage (—O—) may be positioned on any of the remaining fourcarbons of the halogenated phenol ring that are not occupied by theortho-positioned hydroxyl group (—OH) and halogen X. The identity ofeach of the substituents R₁, R₂, R₃, and R₄ of the indole heterocycliccompound (i.e., a hemi-indigo compound) may vary and may include, forexample, a hydrogen, a hydroxyl, a sulfhydryl, an alkyl, a halogen, anamino, a nitro, etc. As described above, the identity of each of theother substituents present on the phenol ring may also vary. Forexample, substituents R₅, R₆ and R₇ on the phenol ring may include ahydrogen, a hydroxyl, a sulfhydryl, an alkyl, a halogen, an amino, anitro, etc., groups. However, substituents R₅, R₆ and R₇ may each behydrogen (see Formula 29 in FIG. 28B).

According to embodiments of the present invention in FIG. 28B, when acompound of Formula 29 comes in contact with an oxidizing agent or freeradical, or is present in an oxidizing and/or free radical containingenvironment, the halogen X is cleaved and removed from the phenol ringand replaced with a hydroxyl group. This free radical attack oroxidation of the phenol ring further results in the breaking or cleavageof the ether linkage (—O—) between the indole heterocyclic portion(i.e., a hemi-indigo portion) and the phenol ring to release a reactiveindole heterocyclic compound. In addition, a halide (X⁻) and abenzenetriol-based or hydroxyhydroquinone-based compound (e.g.,1,2,4-benzenetriol) are formed. Two of the indole heterocyclic compoundsformed during the dehalogenation and cleavage reaction may then reactwith each other in a subsequent reaction to form an indigo orindigo-like compound composed of the two indole heterocyclic compoundsjoined by a double bond. The indole heterocyclic compound products ofthe reaction have a strong preference for reacting with themselves toform the indigo or indigo-like compound. Following dehalogenation andcleavage, the hemi-indigo intermediate has a hydroxyl group formed onthe carbon where the ether linkage was located. However, either beforethe intermediate reacts (with like intermediates) to form theindigo-like product or after forming the indigo-like product, thishydroxyl group formed by the reaction undergoes a keto-enol transitionto form a keto group on that carbon (i.e., the third carbon).

According to these embodiments, the six-membered indole ring of theindigogenic compound may be designed to achieve different objectives orproperties, such as to select for optimal characteristics or advantagesbased on color, X-ray profile and residence time (see below). Thevisible or light-interacting properties of the indigo-like compound maydepend on the substituents bound to each of the indole rings. Forexample, the inclusion of halogens and other substituents in theindigogenic compound may affect the color of the indigo-like product ofthe reaction. Generally, the presence of halogens may give indigo-likecompounds color properties that may be detected visually, but othersubstituents may also affect their color. As mentioned above,indigo-like compounds lacking halogen substituents may also bevisualized or detected by exposing the tissue to UV light and detectingfluorescence.

According to some embodiments, an indigogenic or non-indigogeniccompound that forms a detectable product(s) in the presence of FROS maypotentially be used as part of a diagnostic test to determine the amountof systemic FROS load in the body of an individual (instead of or inaddition to detection in a specific tissue). A sample may be taken fromthe body of the individual, such as a blood, sputum or a urine sample,and exposed or combined with the indigogenic or non-indigogenic compoundto test for the amount of detectable product formed in vitro. The samplemay optionally be processed to isolate or concentrate a portion orfraction of the sample prior to being combined with the compound tocarry out the in vitro test. Alternatively, an indigogenic ornon-indigogenic compound may be administered to an individual, and asample, such as a blood, urine or tissue sample or biopsy) may then betaken from the individual (perhaps after a period of time) to test forthe amount of detectable product in the sample. The sample may also beoptionally processed to isolate, purify, extract or concentrate theindigogenic or non-indigogenic compound from the rest of the sample.According to these embodiments, the amount of product formed, asdetected or measured by light measurement (e.g., absorbance, etc.), maybe used to infer the amount of FROS present in a tissue or systemicallyin the body of the individual. As an alternative to indigo-likecompounds, an in vitro test for detecting or measuring other productsformed by the dehalogenation reaction, such as a quinone species, aphenolic species, or a halide (or iodo-tyrosine compounds that may beformed from iodo-thyronine compounds), may also be used followingadministration of an indigogenic compound of the present invention.

In vitro detection methods based on the detection or measurement ofindigo-like compounds or other detectable products (e.g., abenzenetriol-based product, a benzenetetrol-based product, or a halide)formed from starting compound or formula embodiments of the presentinvention by the dehalogenation reaction in the presence of FROS areproposed as a possible replacement for any current methods for detectinginflammation or FROS load in an individual, such as those based on thedetection of C-reactive protein (CRP). For detection methods designedfor measuring general inflammation or FROS load throughout the body ofan individual, systemic samples, such as blood, sputum or urine, may beused. In addition, detection of products formed from the compound orformula embodiments of the present invention may also be used as adiagnostic indicator for progression against disease and/or levels ofFROS exposure during treatment. As another example, diiodotyrosine (DIT)may be a detectable product formed in the presence of FROS duringtreatment with thyroxine.

Another feature of these indigo-like compounds of the present inventionformed in the presence of the FROS is that they have a higher residencetime in the tissue in which they are formed. With reference to FIG. 28,in comparison to the starting indigogenic compound having Formula 28 or29, the indigo-like compound product of these reactions would have amuch higher residence time in the tissue environment where it is formedbecause the indigo-like compound is more hydrophobic and lipophilic (andless soluble) compared to the original or starting indigogenic compoundor precursor of Formula 28 or 29. The increased residence time ofindigo-like products formed from the indigogenic starting compounds ofthe present invention provides another useful feature to exploit fordiagnosis and detection. In other words, the combination of itsdetectability and localization (at least transiently) to sites ortissues where it is formed provides the ability to detect specific sitesor locations of FROS, which may be associated, for example, withparticular sites of inflammation, infection or disease, such as cancer,etc.

According to some embodiments, when a compound of Formula 28 or 29 isconverted into an indigo-like compound having higher residence time in aFROS-containing tissue as described above, the indigo-like compound(especially those with iodine) may be detected by radiologicaltechniques, such as by being radio-opaque when analyzed by radiological,radiographic or X-ray imaging, such as a plain or projection radiograph.Furthermore, halogenated indigo-like compounds may also have adistinctly colored appearance, which may depend on the halogens andother substituents present on the indole heterocyclic rings, which maybe detected by imaging or visualization, such as during surgery. Forexample, the detection or visualization of a colored or radiopaqueportion of a tissue may be used to detect the location or site ofinfection or disease, such as cancerous tumor, etc., which may be usedas part of a screen, test or diagnostic method, such as a mammography,etc. The combination of both colored and radiopaque characteristics ofsome indigo-like compounds of the present invention may be usedtogether, for example, to coordinate procedures during surgery with pre-and/or post-operative radiological imaging of the surgical site.Therefore, one key advantage of some compounds of Formula 28 or 29 isthat effective and targeted delivery of a colored indigo-like compoundto a site of disease of inflammation in the body of an individual may beconfirmed by separate X-ray or other radiological, imaging and/orvisualization techniques. In addition, an indigo-like compoundcontaining a radioisotope (see below) may be used to deliver theradioisotope to a target site with residence time for treatment of adiseased tissue, and the targeted delivery may then be separatelyconfirmed by visualization and/or radiological detection or measurement.According to some embodiments, it is also envisioned that combinationsof different indigogenic compounds may be co-administered to anindividual, and their products from the dehalogenation reaction measuredjointly, subsequently or in parallel by the same or different methods.

According to an exemplary embodiment, the at least transient depositionof a 5-iodo-indigo or 4,5-diiodo-indigo compound formed from theadministration of 5-iodo-indolyl-3′-iodo-4′-hydroxy ether compound (seeFIG. 29B) or the 4,5-diiodo analogue (see FIG. 29C), respectively, maybe detected in situ where formed in the body of an individual by X-rayradiographic detection methods. A4,5-diiodo-indolyl-3′,5′-diiodo-4′-hydroxyl-p-phenol ether compound isalso proposed as an example having an additional substitution on thephenol ring. These iodo-indigo-like compounds formed in highFROS-containing tissues may have a purple or grape color that may bedifficult to visualize in situ by eye relative to surrounding tissueshaving similar coloration. However, since the iodo-indigo compoundsdeposited in the tissue are radio-opaque, X-ray doses and radiographicimaging may be used to detect their at least transient formation inFROS-containing tissues, perhaps by comparison to control tissues (See,e.g., Example 6 below).

Potentially, detection or measurement of the iodo-indigo compound formedmay also be done in vitro by light measurement (e.g., absorbance, etc.)by taking a sample, such as a urine, blood, sputum, or tissue sample orbiopsy, and measuring the amount of iodo-indigo compounds containedtherein. For example, both the mono-iodo indigo-like product and thedi-iodo indigo-like product may be detected by light absorbance in awavelength range from about 300 nm to about 310 nm. Such in vitromeasurement may be done after further processing to extract, purify orisolate iodo-indigo compounds from the rest of the sample and wouldavoid the issue of having similar coloration as intact tissue.

Although the 4,5-diiodo analogue above would produce an indigo-likecompound that is more radio-opaque than the 5-iodo indigo-like product(due to the additional iodine), the presence of the additional iodineson the 4,5-diiodo-indigo-like product may also lead to higher residencetime, and such higher residence time may be less tolerable for safetyreasons and/or may interfere with subsequent or follow up tests andmeasurements. Thus, with any indigogenic compound described herein, thetype and number of halogens on the indigo-like product of the reactionmust be chosen to balance between (i) the strength of signal, colorationor radio-opaqueness of the indigo-like product and (ii) the amount ofresidence time of the indigo-like product in a tissue.

According to another exemplary embodiment,5-Br-4-Cl-Indolyl-3′-Iodo-4′-Hydroxy Ether compound (see FIG. 29A) maybe taken or administered orally or intra-venously followed by anoptional time for in vivo color development in the body or tissue. Asdescribed generally above, the localization of the 5-Br-4-Cl indigo-likecompound product may then be visualized in situ in the tissue whereformed, such as during surgery. The 5-Br-4-Cl indigo-like compound mayhave a visible color (e.g., aquamarine) that is distinguishably visiblefrom surrounding tissues and may thus be used to label diseased tissues(e.g., tumors, etc.). Thus, their site of formation and deposition maybe determined visually, such as during surgery, as an indication orlabeling of tissues in situ of these diseased tissues having high FROS.Alternatively or additionally, the 5-Br-4-Cl indigo-like compound mayalso be detected or measured in vitro by light measurement (e.g.,absorbance, etc.) by taking a sample, such as a urine, blood or tissuesample or biopsy, and measuring the amount of 5-Br-4-Cl indigo-likecompounds therein as described above, which may be done after furtherprocessing to extract, purify or isolate the 5-Br-4-Cl indigo-likecompounds from the rest of the sample. For example, detection ormeasurement may be performed by measuring the light absorbance of the5-Br-4-Cl indigo-like compound at a wavelength within a range from about595 nm to about 605 nm.

According to another set of embodiments, molecules produced by theFROS-mediated reactions described herein may be differentially detectedor measured by other methods, such as mass spectrometry (MS), nuclearmagnetic resonance (NMR) spectroscopy, magnetic resonance imaging (MRI),chemical test, etc., (perhaps in combination with phase separation,chromatography, and/or other method of separation or purification) toquantitate and/or locate their presence and/or site of formation in thebody for diagnostic purposes. Some products of the reaction fromcompound embodiments the present invention may be distinguished by theirappearance with MRI and/or by size or characteristics of peaks displayedby NMR spectroscopy. For NMR spectroscopy, the presence or amount of aproduct in a blood, urine or tissue sample taken from an individual maybe determined.

Compound embodiments of the present invention, such as those representedin FIGS. 1-25, 28 and 29, may further include those compounds containingthe carbon-13 isotope (¹³C) in place of carbon-12 (¹²C), which may bedifferentially detected or measured by NMR or MRI. In particular, thebenzene or phenol rings of these compounds containing ¹³C as one or moreof the carbons of the ring may be differentially detected or measured bythese methods. In addition, compounds containing ¹³C may bedifferentially detected or measured by mass spectrometry (MS)techniques. Because ¹³C is a stable isotope, the isotope itself does notpose a health risk to the individual taking it. Thus, products of thereaction containing ¹³C, including benzenetriol-based products orbenzenetetrol-based products, may be detected or measured by thesemethods.

According to some of these embodiments, any of the indigogenic compoundsin FIGS. 25 and 26 (e.g., according to Formula 25 or 26) may have ¹³C asone or more of the carbons of the six-membered ring of the indoleheterocyclic portion or hemi-indigo portion of the indigogenic compound.As discussed above, when the indigogenic compound is present in a highFROS-containing tissue or environment within the body of an individual,it undergoes a dehalogenation and cleavage reaction to liberate¹³C-containing indole heterocyclic compound products having a strongpreference for reacting with themselves to form the indigo orindigo-like compounds containing the ¹³C in the resident tissue orenvironment. Once the indigo or indigo-like compounds are formed, theywill remain in the tissue where formed with a prolonged residence timeas described herein. These indigo or indigo-like compounds may then bedifferentially detected in situ by MRI of the individual due to thepresence of ¹³C in the six-membered indole ring. The MRI may beconducted such that only a small area, volume or region of the body isimaged, or alternatively such that the whole body of the individual isimaged. Such imaging may be done in connection with imaging of a knownsite of disease or to search for sites of high FROS or inflammation thatmay be indicative of sites of disease, such as cancer.

According to another broad aspect of the invention, a compound accordingto some embodiments may provide targeted delivery of a radioactive orrare stable isotope-containing compound to diseased cells and/or tissue(e.g., cancerous cells or tissues, etc.) to cause diseased cells of thetargeted tissue to die, undergo apoptosis, favorably senesce, stopdividing, differentiate, etc., which may be favorable for the treatmentof the disease. According to these embodiments, a halogenated phenolring compound may be bonded to one or more radioactive isotopes, such asradioactive iodine (e.g., ¹²⁵I, ¹³¹I). A key factor for the effectivedelivery of a radioactive isotope-containing compound to a targetedtissue or cells (e.g., cancerous or diseased cells or tissues) isavoiding as much as possible unwanted accumulation of the radioactivecompound in other normal tissues and cells, while achieving sufficientresidence time in one or more targeted tissues (e.g., cancerous ordiseased cells or tissues) to exert the desired effect.

According to embodiments of the present invention, compounds havingthese balanced properties may include radioactive isotope-containingindigogenic compounds that dissolve in an aqueous solution, but whichform radioactive compounds with high residence time in a targeted tissuefollowing dehalogenation and ether or thioether cleavage in a reactiontriggered by oxidizing agents and/or free radicals present in thetargeted cells or tissue. In other words, much like the drug-linkedhalogenated phenol ether (or thioether) compounds described above, theradioactive isotope-containing halogenated phenol ether (or thioether)compounds of the present invention may behave like a pro-drug. Once theradioactive isotope-containing halogenated phenol ether (or thioether)compounds encounter an oxidizing and/or free radical containingenvironment, the halogenated phenol ether (or thioether) compound maybecome cleaved as a result of a dehalogenation reaction to produce arelatively insoluble radioactive isotope-containing product withrelatively high residence time in the target tissue or cells in which itis formed. Generally speaking, a compound may have a higher residencetime in a targeted tissue if it is more hydrophobic or lipophilic.

Therefore, according to some embodiments of the present invention, aradioactive compound may be designed such that the solubility of theradioactive compound becomes altered in a targeted tissue as a result ofthe dehalogenation and cleavage reaction triggered by oxidative agentsand/or free radicals present in the targeted tissue. According to someof these embodiments, a radioactive compound may be designed such that aradioactive compound is converted in the targeted tissue as a result ofthe dehalogenation and cleavage reaction from being a hydrophiliccompound dissolved in an aqueous solution to a relatively hydrophobic orlipophilic compound with increased residence time in the targetedtissue. It is further possible that the residence time of a product of agiven compound may be engineered depending on the number and/or types ofsubstituents present on the radioactive isotope-containing compound. Asdescribed above, the present invention further encompasses compositionscomprising radioactive compounds of the present invention as well as anysuitable method of treating, administering to, etc., an individual withthese compositions comprising radioactive compounds of the presentinvention, perhaps in combination with a pharmaceutically acceptablecarrier, to an individual or patient.

According to embodiments presented in FIG. 25, the compound of Formula25 or 26 may be used to deliver a radioactive isotope present on theindigogenic compound. The indigo-like compound product formed by thedehalogenation reaction will retain the radioactive isotope and have ahigher residence time (at least transiently) in the targeted tissuewhere it is formed to deliver focused treatment of the radioactiveisotope to the site of its formation. In contrast, the indigogenicprecursor compound would be relatively soluble and would tend tocirculate throughout the body until being expelled or excreted from thebody. According to these embodiments, one or more of variablesubstituents R₁, R₂, R₃, and R₄ of the indole heterocyclic compound(i.e., a hemi-indigo compound) in FIG. 19 may include a radioactiveisotope, such as a radioactive halogen (e.g., ¹³¹I or ¹²⁵I), whichprovides the therapeutic dose of radioactivity for the targeted (i.e.,diseased) tissue.

Examples Example 1: Synthesis of 1-Acetyl-4-Iodo-IndoxylN-Acetyl-3-Iodo-2-Methyl Aniline

Charge a 5 L, 3 neck flask equipped with a mantle, stirrer, condenser,with 708 grams (5M) 3-Iodo-2-Methyl Aniline, followed by 700 ml glacialacetic acid. Add in a stream of 520 grams (5.1M) acetic anhydride andallow the solution to come to a gentle reflux for an hour. The solutionis allowed to cool and poured in a stream in a large container of 8 Lice water. The product will crystallize immediately and is filtered andsqueezed under vacuum and air-dried. Yield was 900 grams (Theoreticalyield=918 g).

N-Acetyl-6-Iodo Anthranilic Acid

Charge a 22 L flask equipped with a stirrer, thermometer, condenser andheating mantle with 616 grams Magnesium Sulphate (heptahydrate) followedby 10 L water, and 800 grams N-Acetyl-3-Iodo-2-Methyl-Aniline. Themixture is stirred and heated to 85° C., over about an hour, and heat isstopped. Potassium Permanganate (1200 grams, 8 mol) is added in portionsover about 2 hours while the temperature rises to 95° C. from theexotherm. After all the KMnO₄ is added, the reaction is stirred for 1hour with the temperature between 80° C. to 90° C. If excess purplepermanganate is present, add 20 to 50 cc of Methanol to quench. Themixture is filtered while still not through a large Buchner funnel, andthe MnO₂ “cake” is washed with hot water. The clear filtrates are cooledto about 20° C., and the acidity is adjusted to pH=1 (paper) with 20%H₂SO₄. The precipitated product is isolated by filtration and dried.Yield was 623 grams (66%) (Theoretical yield=924 grams). Melting point(m.p.) at 202-205° C.

6-Iodo Anthranilic Acid Hydrochloride

Charge a 12 L, 3-neck flask, equipped with a stirrer, condenser, heatingmantle and thermometer with N-Acetyl-6-Iodo-Anthranilic acid (400 grams)and 2.5 L concentrated HCl. Adjust the temperature to 50-55° C. andmaintain for 24 hours. Higher temperatures may decompose the product.Chill the reaction to less than 5° C. in an ice bath, filter theproduct, wash the filter “cake” with acetone, then diethylether. Air drythe product. Yield was 340 grams. (Theoretical yield=374.4 grams).Melting point (m.p.) at 176-180° C.

N-(3-Iodo-2-Carboxy Phenyl) Glycine-Potassium Salt

Charge a 5 L, 3 neck flask, equipped with a stirrer, thermometer andheating mantle, with 6-Iodo-Anthranilic acid HCl (416 grams, 0.2 mol),followed by 1 L water and 248 grams (4 mol) KOH in 250 cc water, toresult in a solution with pH=8 to 9. Adjust if necessary. Add sodiumchloroacetate (250 grams, 2.1 mol) and stir the reaction for 18 hours at50-60° C. Cool the reaction to 18 to 20° C., filter off the product, andwash with acetone. Air dry the product. The filtrates will yield about20 grams second crop. Yield was 368 grams (67%). (Theoretical yield=556gm).

3-Iodo-Indoxyl Diacetate

Charge a 5 L, 3 neck flask equipped with a heating mantle, stirrer andcondenser with N-(3-Iodo-2-Carboxy Phenyl) Glycine (250 grams, 0.8 mol),fused Sodium Acetate (200 grams) and 1.5 L acetic anhydride. Heat themixture to gentle reflux until CO₂ evolution stops. The hot, darksolution is poured into a beaker and cooled in an ice bath to 18-22° C.to crystallize the product. Filtrates can be concentrated in vacuo toremove most the acetic anhydride, then precipitated by the addition ofice (temperature less than 70° C.) to yield a second crop. Filter, washwith water, and dry. Re-crystallize from hot acetone (about 1 gram/10cc) or hot ethyl acetate (about 1 gram/10 cc). Yield was 165-180 gramsof well-formed crystals. Melting point (m.p.) at 150-152° C. Shows 1spot on TLC in CH2Cl2:MeOH (95:5).

4-Iodo-N-Acetyl Indoxyl

Equip a 2 L beaker with a large magnetic stirrer in an ice bath. Add in600 cc of 90% H₂SO₄ (535 cc H₂SO₄ into 65 cc H₂O) and cool to 20° C. Addthe 3-Iodo-Indoxyl Diacetate (128 grams, 0.39 mol) in portions over 20minutes, with good mixing, keeping temperature less than 28° C. Stir theresulting solution for an additional 60 minutes at 18 to 22° C., andpour in a stream into 2 L of ice and water mix, with good mixing. Thesettled product is filtered, washed with ice water, and the filter“cake” is mixed with 1 L CHCl₃. The aqueous phase is separated, and theorganic phase concentrated to a solid in vacuo. The product is slurriedwith 0.6 L n-Hexane, filtered, washed with minimal n-Hexane and dried.Yield was 104 gm. (88%). (Theoretical yield=121.6 grams). Melting point(m.p.) at 166° C.

Example 1A: Synthesis of 1-Acetyl-4,5-Diiodo-IndoxylN-(3-Iodo-2-Carboxy-Phenyl) Glycine

Potassium Salt of Example 1 was iodinated in the 4-position bysuspension (35.7 grams, 0.1 mol) in 150 ml 1.0 N HCl and cooled to about20° C. A second solution of 100 ml 1.0 N HCl containing ICl (20 grams,0.125 mol) was added to the suspension with stirring and reacted for 6hours at about 20 C. The settled product was collected by filtration andre-crystallized from ethanol/water to yield 28.2 gram (84%), m.p.182-186 C. The Diiodo indoxyl product is produced in the subsequentsteps described in Example 1, starting with ring closure and acetylationin acetic anhydride.

Example 2: Synthesis of 1-Acetyl-5-Br-4-Cl-Indoxyl

1-Acetyl-5-Br-4-Cl-Indoxyl was synthesized according to the methodsdescribed in Example 1 above for 5-Iodo-Indoxyl, by utilizing2-Methyl-3-Chloro-Aniline as the starting material and including abromination step. Specifically, the resultingN-(3-Chloro-2-Carboxy-Phenyl) Glycine (267.6 grams, 1.0 mol) isbrominated by mixing with 550 cc glacial acetic acid, followed byaddition of 52 cc of liquid Bromine to the vigorously stirredsuspension. Bromination is exothermic and results in complete solutionfollowed by precipitation of the product during the last 10 cc ofBromine addition. The reaction was diluted with 2 L of ice water and thebrominated product was isolated by filtration and air dried to yieldabout 240 grams. Melting Point (m.p.) 176-178 C. The remainingprocedures described in Example 1 result in the desired1-Acetyl-5-Br-4-Cl-Indoxyl.

Other syntheses of ring substituted indoxyl and indigo compounds aredescribed, for example, in Holt, S. J., “General Cytochemical Methods”J. F. Danielli, Ed., Academic Press, New York, N.Y., p. 375 (1958), theentire contents and disclosure of which are incorporated herein byreference, wherein the 4,5,6 indoxyl positions can be substituted,individually and in combination, and are anticipated as Br, Cl, and I.These compounds may have advantages of solubility, tissue distribution,residence time, lower toxicity, ease of synthesis and quality of theindigo precipitate for the intended purpose as described in the presentinvention.

Example 3: Synthesis of 1-Oxaspiro-3,5-Diiodo-Bicyclooctadiene-6-One

This synthesis was adapted and extended from prior works. See, e.g.,Salamonczyk, G. M. et al., Tetrahedron Letters, 38(40): 6965-6968(1997), the entire contents and disclosure of which are incorporated byreference.

P-hydroxy benzaldehyde was diiodinated, followed by reduction of thealdehyde to the benzyl alcohol product. The alcohol was oxidized to theepoxy and purified to yellow orange crystals by removal of hydrophiliccomponents by silica gel chromatography:

A solution of p-hydroxybenzaldehyde (31.0 grams, 0.25 mol) was preparedin 450 ml 20% HCl by heating to 75° C. in a stirred reaction vessel. Asecond iodinating solution was prepared by dissolving 81.25 grams ICl to125 ml 20% HCl. This solution was added to the first solution over about5 minutes (no exotherm). The reaction temperature was raised to 55° C.for about 90 minutes as the reaction becomes clear and yellow. Thereaction was poured into 4 L of ice-cold water and allowed toprecipitate overnight. The product was isolated by filtration, washedwith water, dried down in vacuuo with rubber dam (50° C.). Yield was79.1 grams of off-white powder (85% of theoretical yield). The diiodoproduct can be purified by dissolving as a 10% solution in hot ethanoland precipitation by addition of hot water and cooling on ice withstirring. Melting Point (M.P).: at 201-203° C. A second crop containingmonoiodinated product can be obtained by adding cold water and storageat 4° C.

The benzyl alcohol product was formed by reaction of a solution of3,5-Diiodo-4-Hydroxy-Benzaldehyde (49.6 grams, 0.133 mol) in 0.665 Lisopropanol. Sodium borohydride (8 grams) was added with stirring, andthe reaction was warmed to 82° C. over about 10 minutes to becomehomogeneous. The entire reaction was treated with 3 N HCl (58 ml) topH=5. The precipitate was not removed. Water was added all at once atambient temperature with stirring. The boric acid will dissolve, and thedesired benzyl alcohol product will form over about 10 minutes. Thereaction was cooled on ice to less than 15° C. to fully precipitate andisolate the product by filtration, which was then washed with minimalcold water. The filter cake was dried in vacuo at 50° C. Yield was 40grams of off-white crystals. Melting Point (M.P.) at 139-140° C.

The epoxide function was formed from the alcohol (16 grams, 0.425 mol)by dissolving in a mixture of ethyl acetate (128 ml), acetic acid (102ml) and water (13 ml) and treating with sodium bismuthate (23.9 grams,0.085 mol) at 36° C. for 4 hours. The boric acid precipitate wasfiltered off, and 200 ml of toluene was added to the filtrate. Thephases were separated, and the organic phase was dried with anhydroussodium sulfate. The organic phase was filtered through anhydrous silica,and the filtrate was dried down to form the crystalline diiodo-epoxyproduct. Yield 8.9 gm (42% of theoretical yield) containing less than 8%of the mono-iodo substituted epoxy product.

Example 4: Synthesis of 5-Iodo-Indolyl-3′,5′-Diiodo-4′-hydroxyl-p-PhenolEther

A suspension of 3-Hydroxy-5-Iodo-Indole Acetate (8.30 grams, 0.02 mol)was prepared in was prepared as a suspension in 1 L of 50 mM sodiumborate buffer, pH=8.0. The Diiodo Epoxy reagent from Example 3 (8.25grams, 0.022 mol) was added as a solution in 200 ml of DMF, the cloudysuspension was reacted with stirring for 18 hours at about 20 C, and theprecipitated product allowed to settle. The supernatant solution wasdecanted, and the product collected by filtration and washed withacetone prior to drying in vacuo. The final product (12.3 grams) wasdeacetylated in 123 ml anhydrous methanol containing 20 mg sodiummethoxide. The solution will clarify followed by precipitation of thefinal product (11.6 grams, 0.016 mol) at 81% yield based on thediiodo-indole.

Example 4A: Synthesis of4,5-Diiodo-Indolyl-3′,5′-Diiodo-4′-Hyroxy-p-Phenyl Ether

This product was produced as in Example 4 except that the Diiodo Indoxylof Example 1A is utilized. All remaining steps are the same with a yieldof 12.4 grams (85%).

Example 5: Synthesis of5-Bromo-4-Chloro-3′,5′-Diiodo-4′-Hydroxy-p-Phenol Ether

The diiodo epoxy reagent of Example 3 was reacted with the product ofExample 2, 5-Br-4-Cl-Indolyl Acetate (8.24 g, 0.02 mol), and asdescribed in Example 4. The final product was formed by deacetylation in123 ml of anhydrous methanol containing 20 mg of sodium methoxide.

Example 6: X-Ray Detection of Mouse Tumors with Iodo-Indigo Compound

As described above, oxidative foci or tumors may be identified by X-rayradiographic imaging of animals following administration of anindigogenic compound of the present invention. The radio-opaqueindigo-like product formed and deposited with residence time inFROS-containing tumor tissues may then be detected.

In this example, female C3H/HeN mice were obtained as multiparousretired breeders (i.e., after 3 to 4 litters) that were positive for amammary tumor virus. See, e.g., Sellitti, D. F., Tseng, Y-C., andLatham, KR., “Effect of 3,5,3′-Triiodo-L-thyronine on the Incidence andGrowth Kinetics of Spontaneous Mammary Tumors in C3H/HeN Mice,” CancerResearch, 41: 5015-19 (1981), the entire contents and disclosure ofwhich are incorporated herein by reference. Mice showing spontaneoustumors were given 10 mg of 5-Iodo-Indoxyl-3′,5′-Diiodo-4′-hydroxy ethersubstrate (product of Example 4) by gavage. These mice were thensubjected to X-ray imaging of the tumors about two hours after being fedthe iodo-indigogenic compound. Mice that were treated with theiodo-indigogenic compound showed radio-opaque tumor regions or foci byX-ray demonstrating that the 5,5′-diiodo-indigo-like product was formedand deposited in the oxidative tumor tissues (See FIG. 30, bottompanel). In contrast, control X-ray images of the same mice prior totreatment did not show these foci (See FIG. 30, top panel). Whendeveloped, the X-ray film appears dark in areas where more transmissionoccurs and light in areas where less transmission occurs.

As a result of handling the animals and keeping them in cages, some ofthe mice that were administered the 5-iodo-indigo compound experiencedvarious small injuries or wounds (e.g., cuts, scratches, etc.). Whensome of these animals were subjected to X-ray imaging, a strongdetection was observed at the sites of the wound or injury (data notshown). Without being bound by any theory, it is believed that a localinfection and/or wound healing mechanisms were responsible for high FROSat these sites that led to local production of high levels of thedetectable radio-opaque indigo-like product.

Example 7: Administering 5-Br-4-Cl-Indolyl-3′-Iodo-4′-Hydroxy Ether forColor Detection

According to one embodiment, patients may be given an amount of5-Br-4-Cl-Indolyl-3′,5′-Diiodo-4′-Hydroxy-Ether (e.g., about 200 mg)orally or intra-venously followed by an optimal time for in vivo colordevelopment in the body or tissue (e.g., for about two hours). Theformation of 5,5′-Dibromo-4,4′-Dicloro indigo in tissue locations may beobserved macroscopically and used as a diagnostic indicator for furthertreatment (eg. Surgical removal). Alternatively, urine, blood or othertissue biopsy or samples may then be taken from the patient forabsorption or optical density (OD) or other analytical measurement ofthe 5-Br-4-Cl Indigo compound formed. Extraction of the indigo-likecompound from the tissue or urine sample with chloroform or othersolvent or assay may be used to minimize, reduce or eliminate substancesthat may compete or alter indigo detection and quantification.

Example 8: Synthesis of 3-Hydroxy-3′,5′-Diiodo-Thyronimine

The general synthesis scheme includes the formation of the ring etherlink under basic conditions followed by reaction with nitromethane atthe aldehyde. The ring nitro group is then reduced to the amine,diazotized and converted to the hydroxyl product by boiling in water.Reaction with hydroquinone instead of p-methoxyphenol eliminates needfor subsequent de-blocking, but results in slightly lower product yield.The product is reduced to yield the amine, and iodination yields thefinal product:

P-hydroxy phenol (100 g, 0.81 mol) was reacted under reflux for 1.5hours with 3-Nitro-4-Chloro-Benzaldehyde (100 g, 0.54 mol) in 1.1 Lwater containing 41.5 g potassium carbonate and 5.35 g sodiumbisulphate. The reaction mix was poured into 8 L of water with rapidstirring and allowed to precipitate for 18 hours. The precipitate wasisolated by filtration and dissolved in 500 ml hot ethanol, then cooledto obtain 66 grams of a yellow, microcrystalline precipitate (66 grams)in about 45% yield that is isolated by filtration and washing withn-propanol. This vacuum-dried product was suitable for the next step andwas stored under dry argon to protect the aldehyde from oxidation.

Nitromethane (32 gm, 28.2 ml, 0.52 mol) and the aldehyde (136.55 g, 0.5mol) were suspended in 1.0 L ethanol in a 5 L reaction vessel withstirring and cooled to less than 10° C. The reaction was initiated bythe slow addition of a solution containing 50 ml water, 35 g potassiumhydroxide and 100 ml methanol while maintaining the reaction temperatureto less than 10° C. A thick precipitate was formed after an additional15 minutes of reaction, and the product was fully precipitated by theaddition of 2.5 L isopropyl alcohol. The potassium salt precipitate wasisolated by filtration, and the filter cake was washed with 2 floods ofisopropyl alcohol prior to drying in vacuum oven at 50 C to yield 160 gm(86%) of product, suitable for ring nitro group reduction.

The potassium salt (44.6 gm, 0.12 mol) was suspended in 250 ml methanol,and a solution containing 110 ml water, 18 gm NaHS (monohydrate) and 150ml methanol was prepared in a separate container. This solution wasadded with mixing to the solution of the potassium salt and reactedunder reflux for about 60 minutes. Cool the reaction to less than 20°C., and 1.2 L ice cold 0.5 N sulfuric acid was added with mixing. Thesettled precipitate was isolated by filtration and washed with coldwater and rubber dam. The product was dried in vacuo at 50° C. Yield wasabout 35 grams (75% theory) of a yellow amorphous powder suitable fordiazotization. The side chain amide was protected from diazotization.

The amine (23.0 gm, 0.06 mol) was suspended in 140 ml concentratedsulfuric acic, with cooling and temperature monitoring and cooled toless than 10° C. A solution of sodium nitrite (4.14 gm, 0.06 mol) wasprepared in 60 ml concentrated sulfuric acid and cooled to less than 10°C. This solution was added to the amine solution with adequate stirringwhile maintaining the reaction at less than 10° C. The reactionproceeded for 18 hours and then the exothermic reaction was warmed to110° C. with nitrogen evolution to convert the diazo function to thehydroxy. The reaction was poured into 880 grams of ice with goodstirring, diluted with 3 L cold water, and the precipitated product wasallowed to settle. The supernatant was decanted, and the product wasisolated by filtration and washed with cold water. Yield was 12.5 grams(73% theory).

The side-chain amide was further reduced to the primary amine with RedAlprior to iodination to from the final product as the HCl salt.Diiodination of the 3,4′-Dihydroxy product occurred by suspending thedi-hydroxy compound (31 grams) in 350 ml of 20% HCl. A second solutioncontaining 125 ml of 20% HCl and 81.25 grams ICl was added in a steadystream (no exotherm). Mono-Iodination with 42.0 gm ICL was used and wasadded over 1 hour. at 4° C., followed by heating to 55° C. The Diiodoreaction turned yellow over about 1.5 hours at 55° C. The reaction waspoured into a 5 L vessel, and 3 L of water was added with active mixing.Precipitation was performed with continued stirring for 12 hours, andthe product was isolated by filtration. The filter cake was washed withwater. The dioxane purified product was dried in vacuuo at 50° C. Yieldwas 52 grams (89% of theoretical yield) of a sl. off-white product. MP231-236 dec. HNMR (AcetoneD6. 270 MHz): 2.63-2.65 (m, 2H, CH2),2.91-2.98 (m, 2H, CH2NH2), 3.61 (contam. Dioxane), 3.81 (m, 4H, OH, OH,NH2) 6.10 (m, 1H, pos 3 aromatic, 6.71-6.76 (m, 2H, pos. 2,6 aromatic),7.44-7.46 (2H, pos 2′,6′ aromatic). CHNI: carbon (C) (34.02 found, 33.81theory); hydrogen (H) (3.45 found, 2.60 theory); nitrogen (N) (2.79found, 2.80 theory); and iodine (I) (50.26 found, 51.11 theory).

Example 9: Synthesis of 3,5-diiodo-4-hydroxy-(N-Acetyl Tryptamine)

Serotonin was treated with acetic anhydride by standard methods, and theN-Acetyl Tryptamine (20.30 gm, 0.1 mol) was suspended in 1 L of 50 mMsodium borate buffer, pH=8.0. The Diiodo Epoxy reagent of Example 3(37.5 grams, 0.1 mol) was added as a solution in 200 ml of DMF, thecloudy solution was reacted with stirring for 18 hours, and theprecipitated product was allowed to settle. The supernatant solution wasdecanted, and the product was collected by filtration and washed withacetone prior to drying in vacuo. The product (46.0 grams) wasde-acetylated in 240 ml anhydrous methanol containing 50 mg sodiummethoxide. The solution was allowed to clarify, and was followed byprecipitation of the final product (41.6 grams, 0.072 mol) at 72% yieldbased on the N-Acetyl Tryptamine.

Example 10: Synthesis of 3,3′-Diiodo-4-4′-Dihydroxy-Diphenyl Ether

Di-hydroxy-di-phenyl ether (50.25 gm, 0.28 mol) was dinitrated at the3,3′ positions by suspending in 342 ml of water with cooling, whiletreating slowly with 265 gm of concentrated nitric acid. After all ofthe nitric acid was added, the solution became homogeneous. The reactionwas exothermic and was kept at less than 25° C. while the nitrationproduct precipitates over about 5 hours. The crystals were collected byfiltration and dissolved in minimal hot water, and the solution wasadjusted to pH=6 with aqueous ammonia. Crystals of the dinitro productwere immediately precipitated for isolation by filtration. A furthercrystallization from water with carbon decolorization was done toprovide a product suited to reduction: 146 gm (0.5 mol) of this productwas dissolved in 1.5 L methanol and reduced under pressure with 8.0 gmof Paladium/Charcoal. When completed, the filtrate was evaporated invacuo at less than 30° C. The residue was purified from hot ethanol toyield about 43 grams of product. This product (40 grams) was dissolvedin 80 ml acetic acid and added slowly to 40 ml concentrated sulfuricacid with stirring, keeping the temperature below 20° C. This solutionwas added carefully over several hours at about 0° C. to a solutioncontaining 125 ml concentrated sulfuric acid and 17.5 gm of sodiumnitrite. The reaction was continued for another hour at 0° C. A secondsolution was prepared by adding sodium iodide (80 gm), iodine (67 gm),urea (10 gm) in 1300 ml water, and covered with 250 ml of chloroform andthe amine solution was added slowly. The temperature rose as thereaction continued. After about an hour, the chloroform layer was saved,and the aqueous layer was extracted 2 more times with 200 ml ofchloroform. The combined organic portion was extracted with water andthe dried under vacuum in a 40 C water bath. The final product waspurified from hot ethanol. Yield was 58 grams.

Example 11: 4′-Hydroxy-3′-Iodo-6-Mercaptopurine Ether

The 6-thio-ether linked compound was formed by dissolving6-Mercaptoguanine, monohydrate (20.4 gm, 0.12 mol) and2-Nitro-4-Br-Phenol (26.16 gm, 0.12 mol) in acetone (200 ml) at about 20C. A solution of KOH (2 N, 60 ml) was slowly added (4 hr) to the wellmixed reaction. The KBr precipitate was removed by filtration and theacetone filtrate containing the thio-ether product is reduced in volumeunder vacuum until a product precipitate forms. The slurry was placed onice to fully precipitate and the product was isolated by filtration andwashed with minimal cold acetone and compressed with a rubber dam. Thenitro group is reduced to the amine using 12 gm of product dissolved in150 ml anhydrous methanol/25 mg NaOMe, as described in Example 3. Theprecipitated product is isolated by filtration and the amine isdiazotized by dissolution (10 gm) in 100 ml concentrated sulfuric acidand cooled to about 5 C (solution 1). Sodium nitrite (gm) is dissolvedin 50 ml concentrated sulfuric acid, cooled to 5 C (solution 2) andadded with stirring to solution 1, with cooling, at a rate that keepsthe reaction temperature at about 5 C but less than 10 C. The resultingdiazo compound was converted to the iodo product by reaction in 20% HClcontaining ICl as described in Example 3.

Example 12: Synthesis of 3,5-Diiodo-4-Hydroxy-1,3′-Ether-Cortisone

Cortisone (+) 7.2 grams, 0.02 mol, was dissolved in 0.5 L sodium boratebuffer (0.2 M, pH 8), and the Diiodo Epoxy reagent of Example 3 wasadded (14.96 grams, 0.04 mol) as a solution in 200 ml of ethanol. After4 hours of reaction, the precipitated product was isolated byfiltration, washed with acetone and dried in vacuo to yield about 6.2 gmof white microcrystalline product.

While the present invention has been disclosed with reference to certainembodiments, it will be apparent that modifications and variations arepossible without departing from the spirit and scope of the invention asdefined in the appended claims. Furthermore, it should be appreciatedthat all examples in the present disclosure, while illustratingembodiments of the invention, are provided as non-limiting examples andare, therefore, not to be taken as limiting the various aspects soillustrated. The present invention is intended to have the full scopedefined by the language of the following claims, and equivalentsthereof. Accordingly, the drawings and detailed description are to beregarded as illustrative and not as restrictive.

What is claimed is:
 1. A compound having the following chemicalstructure:

wherein R₁ is a drug compound, wherein R₂, R₃ and R₄ are each ahydrogen, a hydroxyl, a sulfhydryl, an alkyl, a halogen, an amino group,or a nitro group, wherein Y is an oxygen, a sulfur, a carbonyl, asecondary amine, a methanediyl, or a sulfoxide, and wherein X is aniodine or a bromine, wherein the drug compound is a steroid.
 2. Thecompound of claim 1, wherein the steroid is a corticosteroid.
 3. Thecompound of claim 1, wherein Y is bonded to a carbon of a carbon ring ofthe corticosteroid.
 4. The compound of claim 2, wherein thecorticosteroid is cortisone.
 5. The compound of claim 2, wherein thecorticosteroid is cortisol.
 6. The compound of claim 2, wherein thecorticosteroid is corticosterone.
 7. The compound of claim 2, whereinthe corticosteroid is hydrocortisone.
 8. The compound of claim 2,wherein the corticosteroid is prednisone.
 9. The compound of claim 2,wherein the corticosteroid is prednisolone.
 10. The compound of claim 2,wherein the corticosteroid is methylprednisolone.
 11. The compound ofclaim 2, wherein the corticosteroid is betamethasone.
 12. The compoundof claim 2, wherein the corticosteroid is dexamethasone.
 13. Thecompound of claim 1, wherein the steroid is estrogen.
 14. The compoundof claim 1, wherein the ether linkage (—Y—) between the halogenatedphenol ring and the drug compound is in the meta-position relative tothe hydroxyl group of the halogenated phenol ring adjacent to thehalogen (X), and wherein the compound has the following chemicalstructure:


15. The compound of claim 1, wherein R₂, R₃, and R₄ are each a hydrogen.16. The compound of claim 1, wherein the ether linkage (—Y—) is para tothe halogen (X).
 17. The compound of claim 1, wherein the ether linkage(—Y—) is ortho to the halogen (X).
 18. The compound of claim 1, whereinthe halogen (X) is an iodine.
 19. A method comprising: selecting anindividual that has been diagnosed as having an arthritis, a boneinjury, a bone degeneration, a joint degeneration, an inflammation, anautoimmune condition, or an infection, and administering apharmaceutical composition to the individual, the pharmaceuticalcomposition comprising a compound and a pharmaceutically acceptablecarrier, wherein the compound has the following chemical structure:

wherein R₁ is a corticosteroid, wherein R₂, R₃ and R₄ are each ahydrogen, a hydroxyl, a sulfhydryl, an alkyl, a halogen, an amino group,or a nitro group, wherein Y is an oxygen, a sulfur, a carbonyl, asecondary amine, a methanediyl, or a sulfoxide, and wherein X is aniodine or a bromine.
 20. The method of claim 19, wherein theadministering step is performed while the individual is experiencingarthritis, bone injury, bone degeneration, joint degeneration,inflammation, autoimmune condition, or infection.